Hepatocellular carcinoma (HCC) is a primary liver tumor that typically arises in a background of chronic liver disease and cirrhosis (Calderaro et al., 2019). One of the key players in the progression of cirrhosis to HCC is the hepatic stellate cell, which is activated during liver damage and differentiates towards a contractile myofibroblast-like cell that deposits extracellular matrix proteins (ECM), such as collagen (Coulouarn and Clément, 2014). Activated stellate cells can induce phenotypic changes in cancer cells through the production of growth factors and cytokines that stimulate tumor cell proliferation and induce a pro-metastatic phenotype (Yu et al., 2013). Malignant hepatocytes secrete high levels of transforming growth factor beta (TGFβ), which can contribute to the activation of stellate cells in the nearby stroma (Giannelli et al., 2014; Nitta et al., 2008; Dooley et al., 2009). These activated stellate cells are then responsible for the deposition of ECM. Several of the ECM-components such as proteoglycans, collagens, laminin, and fibronectin interact with tumor cells and cells in the stroma, which can directly promote cellular transformation and metastasis (Lin et al., 2014; Song et al., 2016). The ECM can also act as a reservoir for growth factors and cytokines, which can be rapidly released to support the tumor's needs. In addition, activated stellate cells contribute to a highly vascularized tumor micro-environment, by secreting pro-angiogenic molecules and by recruiting pro-angiogenic (and pro-tumoral) myeloid and lymphoid derived cell types (Zhang et al., 2017). By constricting the hepatic microvasculature, they also cause hypoxia, which contributes to the angiogenic switch and can induce a more aggressive tumor phenotype (Taura et al., 2008). It is therefore not surprising that tumor cells actively secrete growth factors (such as TGFβ) to induce activation and migration of stellate cells, which creates a fibrotic environment that further supports and enhances tumor progression (Coulouarn and Clément, 2014; Caja et al., 2018; Lu et al., 2015). Since activated stellate cells play an essential role in the onset and progression of HCC, blocking their activation has been proposed as a potential therapy for patients with HCC (Carloni et al., 2014). One strategy to prevent stellate cell activation, is by blocking the IRE1α-pathway of the unfolded protein response (UPR) (Heindryckx et al., 2016; Liu et al., 2019).

The UPR serves to cope with the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) in an attempt to restore protein folding, increase ER-biosynthetic machinery and maintain cellular homeostasis (Schröder and Kaufman, 2005). It can exert a cytoprotective effect by re-establishing cellular homeostasis, while apoptotic signaling pathways will be activated in case of severe and/or prolonged ER-stress (Lam et al., 2020). The presence of misfolded proteins is sensed via three transmembrane proteins in the ER: inositol requiring enzyme 1α (IRE1α), protein kinase RNA-like ER-kinase (PERK) and activating transcription factor 6α (ATF6α) (Acosta-Alvear et al., 2018). The development of solid tumors is characterized by uncontrolled growth and proliferation of malignant cells, resulting in a compact mass of cells and a hypoxic tumor micro-environment, two conditions that are well-characterized ER-stress inducers. Therefore, it is not surprising that activation of the UPR represents a major hallmark of several solid tumors, such as breast cancer (Liang et al., 2018), colon cancer (Li et al., 2017b), and HCC (Vandewynckel et al., 2013). The induction of the UPR in cancer cells may serve as a double-edged sword, which can aid tumor progression as well as prevent tumor growth in a context-dependent manner. Persistent ER-stress can activate pathways that induce cell death, effectively eliminating cells with a potential to become malignant. On the other hand, tumor cells may hijack the ER-stress pathways to provide survival signals required for uncontrolled growth and eventually avoid apoptosis (Kim et al., 2015). Activation of the UPR has also been shown to affect different fibrotic diseases (Heindryckx and Li, 2018), including non-alcoholic fatty liver disease (Bandla et al., 2018; Kwanten et al., 2016; Dasgupta et al., 2020), hepatitis-B-induced carcinogenesis (Li et al., 2017a), and biliary cirrhosis (Sasaki et al., 2015). We have previously shown that inhibiting the IRE1α-branch of the UPR-pathway using 4μ8C, blocks TGFβ-induced activation of fibroblasts and stellate cells in vitro and reduces liver fibrosis in vivo (Heindryckx et al., 2016). In the current study, our aim was to define the role of IRE1α in the cross-talk between hepatic stellate cells and tumor cells in liver cancer. We show that pharmacologic inhibition of the IRE1α-signaling pathway decreases tumor burden in a chemically induced mouse model for HCC. Using several in vitro co-culturing methods, we identified that blocking IRE1α in hepatic stellate cells prevents their activation. This then decreases proliferation and migration of tumor cells in co-cultures, in addition to the direct effect of inhibiting IRE1α in tumor cells. Our results also indicate that there are cell-line-specific differences in how cells respond to IRE1α-inhibition, including differences in the IRE1α-dependent generation of reactive oxygen species.

There is increasing evidence that ER-stress and activation of the UPR play an essential role during hepatic inflammation and chronic liver disease. We have previously shown that inhibition of IRE1α prevents stellate cell activation and reduces liver cirrhosis in vivo (Heindryckx et al., 2016). In this report, we further define a role of the IRE1α-branch of the UPR in the interaction between tumor cells and hepatic stellate cells. We also show that IRE1α could form a valuable therapeutic target to slow down the progression of hepatocellular carcinoma, both through the effect on stromal cells and via the direct effect on cancer cells.

Activated stellate cells play an important role in promoting tumorigenesis and tumors are known to secrete cytokines, such as TGFβ, which activate stellate cells and thereby creates an environment that helps to sustain tumor growth (Heindryckx, 2014). Since over 80% of HCC arises in a setting of chronic inflammation associated with liver fibrosis, targeting the fibrotic tumor micro-environment is often proposed as a valuable therapeutic strategy for HCC-patients (Coulouarn and Clément, 2014). We and others have shown that ER-stress plays an important role in stellate cell activation and contributes to the progression of liver fibrosis (Heindryckx et al., 2016; Koo et al., 2016; Hernández-Gea et al., 2013; Kim et al., 2016; Mao and Fan, 2015). The mechanisms by which the UPR promotes stellate cell activation have been attributed to regulating the expression of c-MYB (Heindryckx et al., 2016), increasing the expression of SMAD-proteins (Koo et al., 2016) and/or by triggering autophagy (Kim et al., 2016; Mao and Fan, 2015).

In our study, we show that IRE1α plays an important role in stellate cell – tumor cell interactions and that pharmacological inhibition of IRE1α-endoribonuclease activity slows down the progression of HCC in vivo. We demonstrate that tumor cells can induce the IRE1α-branch of the UPR in hepatic stellate cells, thereby contributing to their activation and creating an environment that is supportive for tumor growth and metastasis. By co-culturing stellate cells with tumor cells, we mainly observed an increase of the IRE1α-branch of the UPR; however, it is important to note that HepG2-cells also significantly induced mRNA-expression of EIF2AK3, while Huh7-cells seemed to induce DDIT3 in the LX2-cells. These results indicate that ATF6α and PERK-pathways may also play an important role in the interaction between stellate cells and tumor cells. In our study, we also observe that overall levels of XBP1 (spliced and unspliced) were very low in the LX2 monocultures and LX2 + HepG2 co-cultures treated with 4μ8C. This is likely the result of low baseline levels of total XBP1 in these conditions. Several studies have shown that constitutive levels of total XBP1 can be low (Zeng et al., 2009) and that the levels of spliced and unspliced XBP1 can both increase during ER-stress (Yoshida et al., 2001; Cassimeris et al., 2019; Kishino et al., 2017). The conditions where we observe low levels of both unspliced and spliced XBP1 correspond to those where we expect to see low levels of IRE1α activation and thus possibly suggest that ER-stress increased the levels of total XBP1 in hepatic stellate cells. Another unexpected finding in our study is the predominant cytoplasmic localization of spliced XBP1 in liver tissue. Spliced XBP1 contains a nuclear localization signal and a transcriptional activation domain, which can activate the transcription of the UPR target genes. In our study, we do not observe a clear nuclear expression of spliced XBP1, which is in contrast to the study of Yoshida et al., 2006, which shows that spliced XBP1 predominantly localizes in the nucleus of HeLa-cells exposed to acute ER-stress. This study also describes a mechanism whereby unspliced-XBP1 forms a complex with the spliced isoform, thereby exporting it from the nucleus to the cytoplasm, resulting in subsequent degradation by the proteasome. However, this event has been described during the recovery phase of an acute ER-stress event. In our mouse model, we treated mice with a hepatocarcinogenic compound for 25 weeks, resulting in a chronic inflammation and a subsequent activation of IRE1α-dependent ER-stress pathways. It is therefore not unlikely that different cells in this model are experiencing different phases of ER-stress and recovery. At a higher magnification, it becomes clear that the expression of spliced XBP1 is not only cytoplasmic but some staining appears peri-nuclear and nuclear. This could represent different stages of ER-stress activation and recovery in different cell populations; however, more experiments would be needed to verify this hypothesis.

Our results show that TGFβ-secretion by tumor cells could be in part responsible for activating stellate cells and for inducing the IRE1α-branch of the UPR. However, this seems to depend on the cell lines used, as the effect was not seen in the LX2 and HepG2 co-cultures. In these co-cultures, an autocrine signaling mechanism may be playing a role in the LX2-cells and the HepG2 cells may even prevent this. One possible alternative mechanism is through CCN protein upregulation, as this has been shown to induce ER-stress and UPR-activation in both stellate cells and hepatocytes by in vitro and in vivo approaches. CCN proteins are ECM-associated secreted proteins which play a role in a with a wide array of important functions, such as wound healing and tumorigenesis (Park et al., 2019). Adenoviral CCN gene transfer and overexpression of CCN proteins have been shown to induce ER-stress-mediated stellate cell senescence and apoptosis in later stages of fibrosis, consequently contributing to fibrosis resolution (Borkham-Kamphorst et al., 2016; Borkham-Kamphorst et al., 2018). While ER stress is known to play a key role in stellate cell activation and hepatocyte apoptosis during the fibrosis progression, inducing ER-stress-mediated apoptosis in activated stellate cells in advanced stages of fibrosis could be a relevant therapeutic strategy to attenuate liver fibrosis (Borkham-Kamphorst et al., 2016; Borkham-Kamphorst et al., 2018).

Activated stellate cells are known to enhance migration and proliferation of tumor cells in vitro (Song et al., 2016) and in vivo (Amann et al., 2009), by producing ECM-proteins and by secreting growth factors. Extracellular matrix proteins such as collagen can act as a scaffold for tumor cell migration (Han et al., 2016), alter the expression of MMPs (Song et al., 2016) and induce epithelial-mesenchymal transition (Kumar et al., 2014). Activated stellate cells are also an important source of hepatocyte growth factor, which promotes proliferation, cell invasion, and epithelial-mesenchymal transition via the c-MET signaling pathway (Liu et al., 2016). Interestingly, blocking IRE1α in the stellate cell population reduced tumor-induced activation toward myofibroblasts, which then decreases proliferation and migration of tumor-cells in co-cultures. This suggests that targeting the microenvironment using an ER-stress inhibitor could be a promising strategy for patients with HCC.

The UPR has been described as an essential hallmark of HCC (Shuda et al., 2003), although its role within tumorigenesis remains controversial (Vandewynckel et al., 2013). While a mild-to-moderate level of ER-stress leads to activation of the UPR and enables cancer cells to survive and adapt to adverse environmental conditions, the occurrence of severe or sustained ER-stress leads to apoptosis. Both ER-stress inhibitors and ER-stress inducers have therefore been shown to act as potential anti-cancer therapies (Corazzari et al., 2017). A recent study by Wu et al., 2018, demonstrated that IRE1α promotes progression of HCC and that hepatocyte-specific ablation of IRE1α results in a decreased tumorigenesis. In contrast to their study, we found a greater upregulation of actors of the IRE1α-branch within the stroma than in the tumor itself and identified that expression of these IRE1α-markers was mainly localized within the stellate cell population. An important difference between both studies is the mouse model that was used. While Wu et al used a single injection of DEN, we performed weekly injections, causing tumors to occur in a background of fibrosis, similar to what is seen in patients (Heindryckx et al., 2010). Our in vitro studies with mono-cultures confirm that 4μ8C and transfection with si-IRE1α also has a direct effect on proliferation, migration, and intracellular levels of ROS in HCC-cells – similar to the findings of Wu et al - and the response seems to depend on the tumor cell line. Adding 4μ8C to HepG2-cells significantly increased proliferation, while a significant decrease was seen in the Huh7-cells. This difference in response could be due IRE1α's function as a key cell fate regulator. On the one hand, IRE1α can induce mechanisms that restore protein homeostasis and promote cytoprotection, whereas on the other hand IRE1α also activates apoptotic signaling pathways. How and when IRE1α exerts its cytoprotective or its pro-apoptotic function remains largely unknown. The duration and severity of ER-stress seems to be a major contributor to the switch toward apoptosis, possibly by inducing changes in the conformational structure of IRE1α (Ghosh et al., 2014). The threshold at which cells experience a severe and prolonged ER-stress that would induce apoptosis could differ between different cell lines, depending on the translational capacity of the cells (e.g. ER-size, number of chaperones and the amount of degradation machinery) and the intrinsic sources that cause ER-stress (Cubillos-Ruiz et al., 2017). A study of Li et al., 2012, has specifically looked at how IRE1α regulates cell growth and apoptosis in HepG2-cells. Similar to our findings, they discovered that inhibiting IRE1α enhances cell proliferation, while over-expression of IRE1α increases the expression of polo-like kinase, which leads to apoptosis. Interestingly, polo-like kinases have divergent roles on HCC-cell growth depending on which cell line is used, which could explain the different response to 4μ8C in Huh7 and HepG2-cells (Pellegrino et al., 2010). Studies on glioma cells show that IRE1α regulates invasion through MMPs (Auf et al., 2010). In line with these results, we also detected a reduction of MMP1-mRNA expression after 4μ8C-treatment and observed a direct effect on wound closure in HepG2-cells. These results indicate that IRE1α could play a direct role in regulating tumor cell invasion, in addition to its indirect effect via stellate cells. This is also in line with our findings that silencing IRE1α in the tumor cells affects tumor cell proliferation, although this effect seems to be cell line dependent.

Another possible mechanism that explains the cell line specific differences in response to inhibiting IRE1α, is through the generation of ROS. Studies have shown that IRE1α plays an important role in mediating ROS-generation (Abuaita et al., 2015) and 4μ8C has been described as a potent ROS-scavenger (Chan et al., 2018). IRE1α generates ROS through Ca²⁺-mediated signaling between the IRE1α-InsP3R pathway in the ER and the redox-dependent apoptotic pathway in the mitochondrion, as well as via activation of CHOP, BIP and through XBP1-splicing (Riaz et al., 2020; Zeeshan et al., 2016). In line with these findings, we found a significant reduction in intracellular ROS-levels after treatment with 4μ8C in LX2, HepG2 and Huh7-cells. Interestingly, a similar reduction in ROS-generation as in the 4μ8C-treated LX2-cells was seen after transfection of LX2-cells, while an increase of ROS-generation was noted in the transfected HepG2-cells. These results indicate that the reduction in ROS could partially be explained through the decreased activation of the IRE1α-pathway in the LX2-cells. However, how the IRE1α-pathway affects the generation of ROS, seems to be cell-type dependent, as we see different results in the different cell lines we tested. This is in line with previous studies, which also observed this cell line dependent effect on IRE1α-dependent ROS-generation (Chan et al., 2018; Zeeshan et al., 2016). The HepG2 and Huh7-cell lines used in this study are known to have different sensitivities to doxorubicin, a property that has been ascribed to their differences in intracellular ROS-generation after treatment with this chemotherapeutic agent (Dubbelboer et al., 2019). Alterations in oxidative stress can affect cell proliferation, specifically in cancer cells and stellate cells (Montiel-Duarte et al., 2004). In addition, ROS is one of the critical mediators of stellate cell activation and ECM-production (Kong et al., 2019). Oxidative stress has been recognized as one of the key factors in the pathogenesis of HCC and treatment strategies aiming at controlling oxidative stress have shown promising pre-clinical results (Takaki and Yamamoto, 2015; Uchida et al., 2020). Therefore, an IRE1α-mediated regulation of ROS-generation might be a contributing factor that explains our findings on stellate cell activation and tumor cell proliferation after inhibiting IRE1α with 4μ8C or transfection. However, more research is necessary to further elucidate the role of IRE1α in mediating ROS-generation in different cell types. In addition, since we see a potent decrease on ROS-levels after treatment with 4μ8C, even in the cells that were transfected with si- IRE1α, we cannot exclude that – at least part – of our results could be explained through the off-target effect of 4μ8C as a ROS-scavenger. Inhibiting oxidative stress has been shown to attenuate tumor progression in different pre-clinical models for HCC and ROS is a known contributor to the chronic liver disease and HCC (Tien Kuo and Savaraj, 2006; Klieser et al., 2019). Further research is necessary to assess to which extent the ROS-scavenging effect in our study has influenced cancer progression.

In conclusion, the aim of this study was to define the role of IRE1α in the cross-talk between hepatic stellate cells and tumor cells in liver cancer. We show that pharmacologic inhibition of the IRE1α-signaling pathway decreases tumor burden in a DEN-induced mouse model for HCC. Using several in vitro 2D and 3D co-culturing methods, we show that tumor cells can induce the IRE1α-branch of the ER-stress pathways in hepatic stellate cells and that this contributes to their activation. Blocking IRE1α-in these hepatic stellate cells prevents their activation. This then contributes to a decreased proliferation and migration of tumor cells in co-cultures, in addition to the direct effect of inhibiting IRE1α in tumor cells. Our results indicate that there are cell-line-specific differences in the response to IRE1α-inhibition, including intercellular variations in how blocking IRE1α affects the generation of ROS.

Proteomics data has been deposited in Dryad with the following DOI: https://doi.org/10.5061/dryad.6wwpzgmv2.

1. 1. Heindryckx F

   (2020) Dryad Digital Repository

   Protein expression of hepatocellular carcinoma in a fibrotic liver in mice.

   https://doi.org/10.5061/dryad.6wwpzgmv2

1. 1. Seok JY
   2. Na DC
   3. Woo HG
   4. Roncalli M
   5. Kwon SM
   6. Yoo JE
   7. Ahn EY
   8. Kim GI
   9. Choi J
   10. Kim YB
   11. Park YN

   (2020) NCBI Gene Expression Omnibus

   ID GSE31370. Fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition.

   https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31370

1. 1. Abuaita BH
   2. Burkholder KM
   3. Boles BR
   4. O'Riordan MX

   (2015) The endoplasmic reticulum stress sensor Inositol-Requiring enzyme 1α augments bacterial killing through sustained oxidant production

   mBio 6:e00705.

   https://doi.org/10.1128/mBio.00705-15

   • PubMed
   • Google Scholar
2. 1. Acosta-Alvear D
   2. Karagöz GE
   3. Fröhlich F
   4. Li H
   5. Walther TC
   6. Walter P

   (2018) The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1

   eLife 7:e43036.

   https://doi.org/10.7554/eLife.43036

   • PubMed
   • Google Scholar
3. 1. Amann T
   2. Bataille F
   3. Spruss T
   4. Mühlbauer M
   5. Gäbele E
   6. Schölmerich J
   7. Kiefer P
   8. Bosserhoff AK
   9. Hellerbrand C

   (2009) Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma

   Cancer Science 100:646–653.

   https://doi.org/10.1111/j.1349-7006.2009.01087.x

   • PubMed
   • Google Scholar
4. 1. Auf G
   2. Jabouille A
   3. Guérit S
   4. Pineau R
   5. Delugin M
   6. Bouchecareilh M
   7. Magnin N
   8. Favereaux A
   9. Maitre M
   10. Gaiser T
   11. von Deimling A
   12. Czabanka M
   13. Vajkoczy P
   14. Chevet E
   15. Bikfalvi A
   16. Moenner M

   (2010) Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma

   PNAS 107:15553–15558.

   https://doi.org/10.1073/pnas.0914072107

   • PubMed
   • Google Scholar
5. 1. Bandla H
   2. Dasgupta D
   3. Mauer AS
   4. Nozickova B
   5. Kumar S
   6. Hirsova P
   7. Graham RP
   8. Malhi H

   (2018) Deletion of endoplasmic reticulum stress-responsive co-chaperone p58^IPK protects mice from diet-induced steatohepatitis

   Hepatology Research 48:479–494.

   https://doi.org/10.1111/hepr.13052

   • PubMed
   • Google Scholar
6. Conference

   1. Bise R
   2. Kanade T
   3. Yin Z
   4. Huh SI

   (2011) Automatic cell tracking applied to analysis of cell migration in wound healing assay

   Conf Proc IEEE Eng Med Biol Soc. pp. 6174–6179.

   https://doi.org/10.1109/IEMBS.2011.6091525

   • Google Scholar
7. 1. Borkham-Kamphorst E
   2. Steffen BT
   3. Van de Leur E
   4. Tihaa L
   5. Haas U
   6. Woitok MM
   7. Meurer SK
   8. Weiskirchen R

   (2016) Adenoviral CCN gene transfers induce in vitro and in vivo endoplasmic reticulum stress and unfolded protein response

   Biochimica Et Biophysica Acta (BBA) - Molecular Cell Research 1863:2604–2612.

   https://doi.org/10.1016/j.bbamcr.2016.07.006

   • PubMed
   • Google Scholar
8. 1. Borkham-Kamphorst E
   2. Steffen BT
   3. van de Leur E
   4. Haas U
   5. Weiskirchen R

   (2018) Portal myofibroblasts are sensitive to CCN-mediated endoplasmic reticulum stress-related apoptosis with potential to attenuate biliary fibrogenesis

   Cellular Signalling 51:72–85.

   https://doi.org/10.1016/j.cellsig.2018.07.005

   • Google Scholar
9. 1. Caja L
   2. Dituri F
   3. Mancarella S
   4. Caballero-Diaz D
   5. Moustakas A
   6. Giannelli G
   7. Fabregat I

   (2018) TGF-β and the tissue microenvironment: relevance in fibrosis and Cancer

   International Journal of Molecular Sciences 19:1294.

   https://doi.org/10.3390/ijms19051294

   • Google Scholar
10. 1. Calderaro J
    2. Ziol M
    3. Paradis V
    4. Zucman-Rossi J

    (2019) Molecular and histological correlations in liver Cancer

    Journal of Hepatology 71:616–630.

    https://doi.org/10.1016/j.jhep.2019.06.001

    • PubMed
    • Google Scholar
11. 1. Calitz C
    2. Hamman JH
    3. Fey SJ
    4. Viljoen AM
    5. Gouws C
    6. Wrzesinski K

    (2019) A sub-chronic Xysmalobium undulatum hepatotoxicity investigation in HepG2/C3A spheroid cultures compared to an in vivo model

    Journal of Ethnopharmacology 239:111897.

    https://doi.org/10.1016/j.jep.2019.111897

    • PubMed
    • Google Scholar
12. 1. Calitz C
    2. Pavlović N
    3. Rosenquist J
    4. Zagami C
    5. Samanta A

    (2020) A biomimetic model for liver Cancer to study Tumor-Stroma interactions in a 3D environment with tunable Bio-Physical properties

    JoVE 162:e61606.

    https://doi.org/10.3791/61606

    • Google Scholar
13. 1. Capes-Davis A
    2. Theodosopoulos G
    3. Atkin I
    4. Drexler HG
    5. Kohara A
    6. MacLeod RA
    7. Masters JR
    8. Nakamura Y
    9. Reid YA
    10. Reddel RR
    11. Freshney RI

    (2010) Check your cultures! A list of cross-contaminated or misidentified cell lines

    International Journal of Cancer 127:1–8.

    https://doi.org/10.1002/ijc.25242

    • PubMed
    • Google Scholar
14. 1. Cardiff RD
    2. Miller CH
    3. Munn RJ

    (2014) Manual hematoxylin and eosin staining of mouse tissue sections

    Cold Spring Harbor Protocols 2014:pdb.prot073411.

    https://doi.org/10.1101/pdb.prot073411

    • Google Scholar
15. 1. Carloni V
    2. Luong TV
    3. Rombouts K

    (2014) Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever

    Liver International 34:834–843.

    https://doi.org/10.1111/liv.12465

    • PubMed
    • Google Scholar
16. 1. Cassimeris L
    2. Engiles JB
    3. Galantino-Homer H

    (2019) Detection of endoplasmic reticulum stress and the unfolded protein response in naturally-occurring endocrinopathic equine laminitis

    BMC Veterinary Research 15:24.

    https://doi.org/10.1186/s12917-018-1748-x

    • PubMed
    • Google Scholar
17. 1. Chan SMH
    2. Lowe MP
    3. Bernard A
    4. Miller AA
    5. Herbert TP

    (2018) The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8c, is also a potent cellular antioxidant

    Biochemical Journal 475:923–929.

    https://doi.org/10.1042/BCJ20170678

    • PubMed
    • Google Scholar
18. 1. Corazzari M
    2. Gagliardi M
    3. Fimia GM
    4. Piacentini M
    5. Stress ER

    (2017) Unfolded protein response, and Cancer cell fate

    Frontiers in Oncology 7:78.

    https://doi.org/10.3389/fonc.2017.00078

    • Google Scholar
19. 1. Cormier N
    2. Yeo A
    3. Fiorentino E
    4. Paxson J

    (2015) Optimization of the wound scratch assay to detect changes in murine mesenchymal stromal cell migration after damage by soluble cigarette smoke extract

    Journal of Visualized Experiments 106:e53414.

    https://doi.org/10.3791/53414

    • Google Scholar
20. 1. Coulouarn C
    2. Clément B

    (2014) Stellate cells and the development of liver Cancer: therapeutic potential of targeting the stroma

    Journal of Hepatology 60:1306–1309.

    https://doi.org/10.1016/j.jhep.2014.02.003

    • PubMed
    • Google Scholar
21. 1. Cubillos-Ruiz JR
    2. Bettigole SE
    3. Glimcher LH

    (2017) Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in Cancer

    Cell 168:692–706.

    https://doi.org/10.1016/j.cell.2016.12.004

    • PubMed
    • Google Scholar
22. 1. Dasgupta D
    2. Nakao Y
    3. Mauer AS
    4. Thompson JM
    5. Sehrawat TS
    6. Liao CY
    7. Krishnan A
    8. Lucien F
    9. Guo Q
    10. Liu M
    11. Xue F
    12. Fukushima M
    13. Katsumi T
    14. Bansal A
    15. Pandey MK
    16. Maiers JL
    17. DeGrado T
    18. Ibrahim SH
    19. Revzin A
    20. Pavelko KD
    21. Barry MA
    22. Kaufman RJ
    23. Malhi H

    (2020) IRE1A stimulates Hepatocyte-Derived extracellular vesicles that promote inflammation in mice with Steatohepatitis

    Gastroenterology 159:1487–1503.

    https://doi.org/10.1053/j.gastro.2020.06.031

    • PubMed
    • Google Scholar
23. 1. Dooley S
    2. Weng H
    3. Mertens PR

    (2009) Hypotheses on the role of transforming growth factor-beta in the onset and progression of hepatocellular carcinoma

    Digestive Diseases 27:93–101.

    https://doi.org/10.1159/000218340

    • PubMed
    • Google Scholar
24. 1. Dubbelboer IR
    2. Pavlovic N
    3. Heindryckx F
    4. Sjögren E
    5. Lennernäs H

    (2019) Liver Cancer cell lines treated with doxorubicin under normoxia and hypoxia: cell viability and oncologic protein profile

    Cancers 11:1024.

    https://doi.org/10.3390/cancers11071024

    • Google Scholar
25. 1. Eaton SL
    2. Hurtado ML
    3. Oldknow KJ
    4. Graham LC
    5. Marchant TW
    6. Gillingwater TH
    7. Farquharson C
    8. Wishart TM

    (2014) A guide to modern quantitative fluorescent western blotting with troubleshooting strategies

    Journal of Visualized Experiments 93:e52099.

    https://doi.org/10.3791/52099

    • Google Scholar
26. 1. Fuchs PÖ
    2. Calitz C
    3. Pavlović N
    4. Binet F
    5. Solbak SMØ
    6. Danielson UH
    7. Kreuger J
    8. Heindryckx F
    9. Gerwins P

    (2020) Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment

    Cellular Signalling 72:109661.

    https://doi.org/10.1016/j.cellsig.2020.109661

    • PubMed
    • Google Scholar
27. 1. Ghosh R
    2. Wang L
    3. Wang ES
    4. Perera BGK
    5. Igbaria A
    6. Morita S
    7. Prado K
    8. Thamsen M
    9. Caswell D
    10. Macias H
    11. Weiberth KF
    12. Gliedt MJ
    13. Alavi MV
    14. Hari SB
    15. Mitra AK
    16. Bhhatarai B
    17. Schürer SC
    18. Snapp EL
    19. Gould DB
    20. German MS
    21. Backes BJ
    22. Maly DJ
    23. Oakes SA
    24. Papa FR

    (2014) Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress

    Cell 158:534–548.

    https://doi.org/10.1016/j.cell.2014.07.002

    • Google Scholar
28. 1. Giannelli G
    2. Villa E
    3. Lahn M

    (2014) Transforming growth factor-β as a therapeutic target in hepatocellular carcinoma

    Cancer Research 74:1890–1894.

    https://doi.org/10.1158/0008-5472.CAN-14-0243

    • PubMed
    • Google Scholar
29. 1. Han W
    2. Chen S
    3. Yuan W
    4. Fan Q
    5. Tian J
    6. Wang X
    7. Chen L
    8. Zhang X
    9. Wei W
    10. Liu R
    11. Qu J
    12. Jiao Y
    13. Austin RH
    14. Liu L

    (2016) Oriented collagen fibers direct tumor cell intravasation

    PNAS 113:11208–11213.

    https://doi.org/10.1073/pnas.1610347113

    • PubMed
    • Google Scholar
30. 1. Hang HL
    2. Liu XY
    3. Wang HT
    4. Xu N
    5. Bian JM
    6. Zhang JJ
    7. Xia L
    8. Xia Q

    (2017) Hepatocyte nuclear factor 4A improves hepatic differentiation of immortalized adult human hepatocytes and improves liver function and survival

    Experimental Cell Research 360:81–93.

    https://doi.org/10.1016/j.yexcr.2017.08.020

    • PubMed
    • Google Scholar
31. 1. Heindryckx F
    2. Mertens K
    3. Charette N
    4. Vandeghinste B
    5. Casteleyn C
    6. Van Steenkiste C
    7. Slaets D
    8. Libbrecht L
    9. Staelens S
    10. Starkel P
    11. Geerts A
    12. Colle I
    13. Van Vlierberghe H

    (2010) Kinetics of angiogenic changes in a new mouse model for hepatocellular carcinoma

    Molecular Cancer 9:219.

    https://doi.org/10.1186/1476-4598-9-219

    • Google Scholar
32. 1. Heindryckx F
    2. Bogaerts E
    3. Coulon SH
    4. Devlies H
    5. Geerts AM
    6. Libbrecht L
    7. Stassen JM
    8. Carmeliet P
    9. Colle IO
    10. Van Vlierberghe HR

    (2012) Inhibition of the placental growth factor decreases burden of cholangiocarcinoma and hepatocellular carcinoma in a transgenic mouse model

    European Journal of Gastroenterology & Hepatology 24:1020–1032.

    https://doi.org/10.1097/MEG.0b013e3283554219

    • PubMed
    • Google Scholar
33. 1. Heindryckx F

    (2014) Targeting the tumor stroma in hepatocellular carcinoma

    World Journal of Hepatology 7:165–176.

    https://doi.org/10.4254/wjh.v7.i2.165

    • Google Scholar
34. 1. Heindryckx F
    2. Binet F
    3. Ponticos M
    4. Rombouts K
    5. Lau J
    6. Kreuger J
    7. Gerwins P

    (2016) Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing

    EMBO Molecular Medicine 8:201505925.

    https://doi.org/10.15252/emmm.201505925

    • Google Scholar
35. Data

    1. Heindryckx F

    (authors) (2020) Protein expression of hepatocellular carcinoma in a fibrotic liver in mice

    Dryad Digital Repository.

    https://doi.org/10.5061/dryad.6wwpzgmv2
36. 1. Heindryckx F
    2. Li JP

    (2018) Role of proteoglycans in neuro-inflammation and central nervous system fibrosis

    Matrix Biology 68-69:589–601.

    https://doi.org/10.1016/j.matbio.2018.01.015

    • PubMed
    • Google Scholar
37. 1. Hernández-Gea V
    2. Hilscher M
    3. Rozenfeld R
    4. Lim MP
    5. Nieto N
    6. Werner S
    7. Devi LA
    8. Friedman SL

    (2013) Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy

    Journal of Hepatology 59:98–104.

    https://doi.org/10.1016/j.jhep.2013.02.016

    • PubMed
    • Google Scholar
38. 1. Huang Y
    2. de Boer WB
    3. Adams LA
    4. MacQuillan G
    5. Rossi E
    6. Rigby P
    7. Raftopoulos SC
    8. Bulsara M
    9. Jeffrey GP

    (2013) Image analysis of liver collagen using sirius red is more accurate and correlates better with serum fibrosis markers than trichrome

    Liver International 33:1249–1256.

    https://doi.org/10.1111/liv.12184

    • Google Scholar
39. 1. Kim H
    2. Bhattacharya A
    3. Qi L

    (2015) Endoplasmic reticulum quality control in cancer: Friend or foe

    Seminars in Cancer Biology 33:25–33.

    https://doi.org/10.1016/j.semcancer.2015.02.003

    • Google Scholar
40. 1. Kim RS
    2. Hasegawa D
    3. Goossens N
    4. Tsuchida T
    5. Athwal V
    6. Sun X
    7. Robinson CL
    8. Bhattacharya D
    9. Chou H-I
    10. Zhang DY
    11. Fuchs BC
    12. Lee Y
    13. Hoshida Y
    14. Friedman SL

    (2016) The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy

    Scientific Reports 6:39342.

    https://doi.org/10.1038/srep39342

    • Google Scholar
41. 1. Kishino A
    2. Hayashi K
    3. Hidai C
    4. Masuda T
    5. Nomura Y
    6. Oshima T

    (2017) XBP1-FoxO1 interaction regulates ER stress-induced autophagy in auditory cells

    Scientific Reports 7:4442.

    https://doi.org/10.1038/s41598-017-02960-1

    • Google Scholar
42. 1. Klieser E
    2. Mayr C
    3. Kiesslich T
    4. Wissniowski T
    5. Fazio PD
    6. Neureiter D
    7. Ocker M

    (2019) The crosstalk of miRNA and oxidative stress in the liver: from physiology to pathology and clinical implications

    International Journal of Molecular Sciences 20:5266.

    https://doi.org/10.3390/ijms20215266

    • Google Scholar
43. 1. Kong M
    2. Chen X
    3. Lv F
    4. Ren H
    5. Fan Z
    6. Qin H
    7. Yu L
    8. Shi X
    9. Xu Y

    (2019) Serum response factor (SRF) promotes ROS generation and hepatic stellate cell activation by epigenetically stimulating NCF1/2 transcription

    Redox Biology 26:101302.

    https://doi.org/10.1016/j.redox.2019.101302

    • Google Scholar
44. 1. Koo JH
    2. Lee HJ
    3. Kim W
    4. Kim SG

    (2016) Endoplasmic Reticulum Stress in Hepatic Stellate Cells Promotes Liver Fibrosis via PERK-Mediated Degradation of HNRNPA1 and Up-regulation of SMAD2

    Gastroenterology 150:181–193.

    https://doi.org/10.1053/j.gastro.2015.09.039

    • Google Scholar
45. 1. Krauthamer M
    2. Rouvinov K
    3. Ariad S
    4. Man S
    5. Walfish S
    6. Pinsk I
    7. Sztarker I
    8. Charkovsky T
    9. Lavrenkov K

    (2013) A study of inflammation-based predictors of tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal Cancer

    Oncology 85:27–32.

    https://doi.org/10.1159/000348385

    • PubMed
    • Google Scholar
46. 1. Kumar S
    2. Das A
    3. Sen S

    (2014) Extracellular matrix density promotes EMT by weakening cell–cell adhesions

    Mol. BioSyst. 10:838–850.

    https://doi.org/10.1039/C3MB70431A

    • Google Scholar
47. 1. Kwanten WJ
    2. Vandewynckel Y-P
    3. Martinet W
    4. De Winter BY
    5. Michielsen PP
    6. Van Hoof VO
    7. Driessen A
    8. Timmermans J-P
    9. Bedossa P
    10. Van Vlierberghe H
    11. Francque SM

    (2016) Hepatocellular autophagy modulates the unfolded protein response and fasting-induced steatosis in mice

    American Journal of Physiology-Gastrointestinal and Liver Physiology 311:G599–G609.

    https://doi.org/10.1152/ajpgi.00418.2015

    • Google Scholar
48. 1. Lam M
    2. Marsters SA
    3. Ashkenazi A
    4. Walter P

    (2020) Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress

    eLife 9:e52291.

    https://doi.org/10.7554/eLife.52291

    • PubMed
    • Google Scholar
49. 1. Li X
    2. Zhu H
    3. Huang H
    4. Jiang R
    5. Zhao W
    6. Liu Y
    7. Zhou J
    8. Guo F-J

    (2012) Study on the effect of IRE1α on cell growth and apoptosis via modulation PLK1 in ER stress response

    Molecular and Cellular Biochemistry 365:99–108.

    https://doi.org/10.1007/s11010-012-1248-4

    • Google Scholar
50. 1. Li J
    2. He J
    3. Fu Y
    4. Hu X
    5. Sun L-Q
    6. Huang Y
    7. Fan X

    (2017a) Hepatitis B virus X protein inhibits apoptosis by modulating endoplasmic reticulum stress response

    Oncotarget 8:96027–96034.

    https://doi.org/10.18632/oncotarget.21630

    • Google Scholar
51. 1. Li XX
    2. Zhang HS
    3. Xu YM
    4. Zhang RJ
    5. Chen Y
    6. Fan L
    7. Qin YQ
    8. Liu Y
    9. Li M
    10. Fang J

    (2017b) Knockdown of IRE1alpha inhibits colonic tumorigenesis through decreasing beta-catenin and IRE1alpha targeting suppresses Colon cancer cells

    Oncogene 36:6738–6746.

    https://doi.org/10.1038/onc.2017.284

    • PubMed
    • Google Scholar
52. 1. Liang H
    2. Xiao J
    3. Zhou Z
    4. Wu J
    5. Ge F
    6. Li Z
    7. Zhang H
    8. Sun J
    9. Li F
    10. Liu R
    11. Chen C

    (2018) Hypoxia induces miR-153 through the IRE1α-XBP1 pathway to fine tune the HIF1α/VEGFA Axis in breast Cancer angiogenesis

    Oncogene 37:1961–1975.

    https://doi.org/10.1038/s41388-017-0089-8

    • Google Scholar
53. 1. Lin N
    2. Chen Z
    3. Lu Y
    4. Li Y
    5. Hu K
    6. Xu R

    (2014) Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma

    Hepatology Research 45:326–336.

    https://doi.org/10.1111/hepr.12356

    • PubMed
    • Google Scholar
54. 1. Liu WT
    2. Jing YY
    3. Yu GF
    4. Chen H
    5. Han ZP
    6. Yu DD
    7. Fan QM
    8. Ye F
    9. Li R
    10. Gao L
    11. Zhao QD
    12. Wu MC
    13. Wei LX

    (2016) Hepatic stellate cell promoted hepatoma cell invasion via the HGF/c-Met signaling pathway regulated by p53

    Cell Cycle 15:886–894.

    https://doi.org/10.1080/15384101.2016.1152428

    • PubMed
    • Google Scholar
55. 1. Liu Z
    2. Li C
    3. Kang N
    4. Malhi H
    5. Shah VH
    6. Maiers JL

    (2019) Transforming growth factor β (TGFβ) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation

    Journal of Biological Chemistry 294:3137–3151.

    https://doi.org/10.1074/jbc.RA118.005761

    • Google Scholar
56. 1. Lu YI
    2. Lin NAN
    3. Chen Z
    4. Xu R

    (2015) Hypoxia-induced secretion of platelet-derived growth factor-BB by hepatocellular carcinoma cells increases activated hepatic stellate cell proliferation, migration and expression of vascular endothelial growth factor-A

    Molecular Medicine Reports 11:691–697.

    https://doi.org/10.3892/mmr.2014.2689

    • Google Scholar
57. 1. Mao Y-Q
    2. Fan XM

    (2015) Autophagy: A new therapeutic target for liver fibrosis

    World Journal of Hepatology 7:1982–1986.

    https://doi.org/10.4254/wjh.v7.i16.1982

    • Google Scholar
58. 1. Mazza G
    2. Al-Akkad W
    3. Telese A
    4. Longato L
    5. Urbani L
    6. Robinson B
    7. Hall A
    8. Kong K
    9. Frenguelli L
    10. Marrone G
    11. Willacy O
    12. Shaeri M
    13. Burns A
    14. Malago M
    15. Gilbertson J
    16. Rendell N
    17. Moore K
    18. Hughes D
    19. Notingher I
    20. Jell G
    21. Del Rio Hernandez A
    22. De Coppi P
    23. Rombouts K
    24. Pinzani M

    (2017) Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization

    Scientific Reports 7:5534.

    https://doi.org/10.1038/s41598-017-05134-1

    • PubMed
    • Google Scholar
59. 1. Montiel-Duarte C
    2. Ansorena E
    3. López-Zabalza MJ
    4. Cenarruzabeitia E
    5. Iraburu MJ

    (2004) Role of reactive oxygen species, glutathione and NF-κB in apoptosis induced by 3,4-methylenedioxymethamphetamine (“Ecstasy”) on hepatic stellate cells

    Biochemical Pharmacology 67:1025–1033.

    https://doi.org/10.1016/j.bcp.2003.10.020

    • Google Scholar
60. 1. Nitta T
    2. Kim J-S
    3. Mohuczy D
    4. Behrns KE

    (2008) Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways

    Hepatology 48:909–919.

    https://doi.org/10.1002/hep.22397

    • Google Scholar
61. Conference

    1. Oudin MJ
    2. Weaver VM

    (2016) Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis

    Cold Spring Harbor Symposia on Quantitative Biology. pp. 189–205.

    https://doi.org/10.1101/sqb.2016.81.030817

    • Google Scholar
62. 1. Park M-H
    2. Kim A
    3. Manandhar S
    4. Oh S-Y
    5. Jang G-H
    6. Kang L
    7. Lee D-W
    8. Hyeon DY
    9. Lee S-H
    10. Lee HE
    11. Huh T-L
    12. Suh SH
    13. Hwang D
    14. Byun K
    15. Park H-C
    16. Lee YM

    (2019) CCN1 interlinks integrin and hippo pathway to autoregulate tip cell activity

    eLife 8:e46102.

    https://doi.org/10.7554/eLife.46012

    • Google Scholar
63. 1. Pellegrino R
    2. Calvisi DF
    3. Ladu S
    4. Ehemann V
    5. Staniscia T
    6. Evert M
    7. Dombrowski F
    8. Schirmacher P
    9. Longerich T

    (2010) Oncogenic and tumor suppressive roles of polo-like kinases in human hepatocellular carcinoma

    Hepatology 5:68.

    https://doi.org/10.1002/hep.23467

    • Google Scholar
64. 1. Pinto BI
    2. Cruz ND
    3. Lujan OR
    4. Propper CR
    5. Kellar RS

    (2019) In vitro scratch assay to demonstrate effects of arsenic on skin cell migration

    Journal of Visualized Experiments 144:58838.

    https://doi.org/10.3791/58838

    • Google Scholar
65. 1. Präbst K
    2. Engelhardt H
    3. Ringgeler S
    4. Hübner H

    (2017) Basic colorimetric proliferation assays: mtt, WST, and resazurin

    Methods in Molecular Biology 1601:1–17.

    https://doi.org/10.1007/978-1-4939-6960-9_1

    • PubMed
    • Google Scholar
66. 1. Riaz TA
    2. Junjappa RP
    3. Handigund M
    4. Ferdous J
    5. Kim H-R
    6. Chae H-J

    (2020) Role of endoplasmic reticulum stress sensor IRE1α in cellular physiology, calcium, ROS signaling, and metaflammation

    Cells 9:1160.

    https://doi.org/10.3390/cells9051160

    • Google Scholar
67. 1. Rouillard AD
    2. Gundersen GW
    3. Fernandez NF
    4. Wang Z
    5. Monteiro CD
    6. McDermott MG
    7. Ma'ayan A

    (2016) The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins

    Database 2016:baw100.

    https://doi.org/10.1093/database/baw100

    • PubMed
    • Google Scholar
68. 1. Ruifrok AC
    2. Johnston DA

    (2001)

    Quantification of histochemical staining by color deconvolution

    Analytical and Quantitative Cytology and Histology 23:291–299.

    • PubMed
    • Google Scholar
69. 1. Sasaki M
    2. Yoshimura-Miyakoshi M
    3. Sato Y
    4. Nakanuma Y

    (2015) A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis

    Journal of Gastroenterology 50:984–995.

    https://doi.org/10.1007/s00535-014-1033-0

    • PubMed
    • Google Scholar
70. 1. Schröder M
    2. Kaufman RJ

    (2005) ER stress and the unfolded protein response

    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 569:29–63.

    https://doi.org/10.1016/j.mrfmmm.2004.06.056

    • Google Scholar
71. 1. Seok JY
    2. Na DC
    3. Woo HG
    4. Roncalli M
    5. Kwon SM
    6. Yoo JE
    7. Ahn EY
    8. Kim GI
    9. Choi J-S
    10. Kim YB
    11. Park YN

    (2012) A fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition

    Hepatology 55:1776–1786.

    https://doi.org/10.1002/hep.25570

    • Google Scholar
72. 1. Shuda M
    2. Kondoh N
    3. Imazeki N
    4. Tanaka K
    5. Okada T
    6. Mori K
    7. Hada A
    8. Arai M
    9. Wakatsuki T
    10. Matsubara O
    11. Yamamoto N
    12. Yamamoto M

    (2003) Activation of the ATF6, XBP1 and grp78 genes in human hepatocellular carcinoma: a possible involvement of the ER stress pathway in hepatocarcinogenesis

    Journal of Hepatology 38:605–614.

    https://doi.org/10.1016/S0168-8278(03)00029-1

    • PubMed
    • Google Scholar
73. 1. Song Y
    2. Kim S
    3. Kim KM
    4. Choi EK
    5. Kim J
    6. Seo HR

    (2016) Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids

    Scientific Reports 6:36750.

    https://doi.org/10.1038/srep36750

    • Google Scholar
74. 1. Subramanian A
    2. Tamayo P
    3. Mootha VK
    4. Mukherjee S
    5. Ebert BL
    6. Gillette MA
    7. Paulovich A
    8. Pomeroy SL
    9. Golub TR
    10. Lander ES
    11. Mesirov JP

    (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles

    PNAS 102:15545–15550.

    https://doi.org/10.1073/pnas.0506580102

    • PubMed
    • Google Scholar
75. 1. Takaki A
    2. Yamamoto K

    (2015) Control of oxidative stress in hepatocellular carcinoma: helpful or harmful?

    World Journal of Hepatology 7:968–979.

    https://doi.org/10.4254/wjh.v7.i7.968

    • PubMed
    • Google Scholar
76. 1. Taura K
    2. De Minicis S
    3. Seki E
    4. Hatano E
    5. Iwaisako K
    6. Osterreicher CH
    7. Kodama Y
    8. Miura K
    9. Ikai I
    10. Uemoto S
    11. Brenner DA

    (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis

    Gastroenterology 135:1729–1738.

    https://doi.org/10.1053/j.gastro.2008.07.065

    • PubMed
    • Google Scholar
77. 1. Thanapirom K
    2. Frenguelli L
    3. Al-Akkad W
    4. Zhang Z
    5. Pinzani M
    6. Mazza G
    7. Rombouts K

    (2019) PS-036-Optimization and validation of a novel three-dimensional co-culture system in decellularized human liver scaffold for the study of liver fibrosis and Cancer

    Journal of Hepatology 70:e24.

    https://doi.org/10.1016/S0618-8278(19)30042-8

    • Google Scholar
78. Website

    1. The Human Protein Atlas

    (2019a) Liver cancer

    Accessed September 5, 2019.

    https://www.proteinatlas.org/ENSG00000160691-SHC1/pathology/liver+cancer
79. Website

    1. The Human Protein Atlas

    (2019b) PPP2R5B is prognostic, high expression is unfavourable in liver Cancer

    Accessed September 5, 2019.

    https://www.proteinatlas.org/ENSG00000068971-PPP2R5B/pathology/liver+cancer#imid_9419368
80. Website

    1. The Human Protein Atlas

    (2019c) SPA5 is not prognostic in liver Cancer

    Accessed September 9, 2019.

    https://www.proteinatlas.org/ENSG00000044574-HSPA5/pathology/liver+cancer
81. Website

    1. The Human Protein Atlas

    (2019d) WIPI1 is not prognostic in liver Cancer

    Accessed September 9, 2020.

    https://www.proteinatlas.org/ENSG00000070540-WIPI1/pathology/liver+cancer
82. 1. Tien Kuo M
    2. Savaraj N

    (2006) Roles of reactive oxygen species in Hepatocarcinogenesis and drug resistance gene expression in liver cancers

    Molecular Carcinogenesis 45:701–709.

    https://doi.org/10.1002/mc.20240

    • PubMed
    • Google Scholar
83. 1. Uchida D
    2. Takaki A
    3. Oyama A
    4. Adachi T
    5. Wada N
    6. Onishi H
    7. Okada H

    (2020) Oxidative stress management in chronic liver diseases and hepatocellular carcinoma

    Nutrients 12:1576.

    https://doi.org/10.3390/nu12061576

    • Google Scholar
84. 1. Uhlén M
    2. Fagerberg L
    3. Hallström BM
    4. Lindskog C
    5. Oksvold P
    6. Mardinoglu A
    7. Sivertsson Å
    8. Kampf C
    9. Sjöstedt E
    10. Asplund A
    11. Olsson I
    12. Edlund K
    13. Lundberg E
    14. Navani S
    15. Szigyarto CA
    16. Odeberg J
    17. Djureinovic D
    18. Takanen JO
    19. Hober S
    20. Alm T
    21. Edqvist PH
    22. Berling H
    23. Tegel H
    24. Mulder J
    25. Rockberg J
    26. Nilsson P
    27. Schwenk JM
    28. Hamsten M
    29. von Feilitzen K
    30. Forsberg M
    31. Persson L
    32. Johansson F
    33. Zwahlen M
    34. von Heijne G
    35. Nielsen J
    36. Pontén F

    (2015) Proteomics. Tissue-based map of the human proteome

    Science 347:1260419.

    https://doi.org/10.1126/science.1260419

    • PubMed
    • Google Scholar
85. 1. Vandewynckel YP
    2. Laukens D
    3. Geerts A
    4. Bogaerts E
    5. Paridaens A
    6. Verhelst X
    7. Janssens S
    8. Heindryckx F
    9. Van Vlierberghe H

    (2013)

    The paradox of the unfolded protein response in Cancer

    Anticancer Research 33:4683–4694.

    • PubMed
    • Google Scholar
86. 1. Wu Y
    2. Shan B
    3. Dai J
    4. Xia Z
    5. Cai J
    6. Chen T
    7. Lv S
    8. Feng Y
    9. Zheng L
    10. Wang Y
    11. Liu J
    12. Fang J
    13. Xie D
    14. Rui L
    15. Liu J
    16. Liu Y

    (2018) Dual role for inositol-requiring enzyme 1α in promoting the development of hepatocellular carcinoma during diet-induced obesity in mice

    Hepatology 68:533–546.

    https://doi.org/10.1002/hep.29871

    • PubMed
    • Google Scholar
87. 1. Yoshida H
    2. Matsui T
    3. Yamamoto A
    4. Okada T
    5. Mori K

    (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor

    Cell 107:881–891.

    https://doi.org/10.1016/S0092-8674(01)00611-0

    • PubMed
    • Google Scholar
88. 1. Yoshida H
    2. Oku M
    3. Suzuki M
    4. Mori K

    (2006) pXBP1(U) encoded in XBP1 pre-mRNA negatively regulates unfolded protein response activator pXBP1(S) in mammalian ER stress response

    Journal of Cell Biology 172:565–575.

    https://doi.org/10.1083/jcb.200508145

    • PubMed
    • Google Scholar
89. 1. Yu G
    2. Jing Y
    3. Kou X
    4. Ye F
    5. Gao L
    6. Fan Q
    7. Yang Y
    8. Zhao Q
    9. Li R
    10. Wu M
    11. Wei L

    (2013) Hepatic stellate cells secreted hepatocyte growth factor contributes to the chemoresistance of hepatocellular carcinoma

    PLOS ONE 8:e73312.

    https://doi.org/10.1371/journal.pone.0073312

    • PubMed
    • Google Scholar
90. 1. Zeeshan HM
    2. Lee GH
    3. Kim HR
    4. Chae HJ

    (2016) Endoplasmic reticulum stress and associated ROS

    International Journal of Molecular Sciences 17:327.

    https://doi.org/10.3390/ijms17030327

    • PubMed
    • Google Scholar
91. 1. Zeng L
    2. Zampetaki A
    3. Margariti A
    4. Pepe AE
    5. Alam S
    6. Martin D
    7. Xiao Q
    8. Wang W
    9. Jin ZG
    10. Cockerill G
    11. Mori K
    12. Li YS
    13. Hu Y
    14. Chien S
    15. Xu Q

    (2009) Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow

    PNAS 106:8326–8331.

    https://doi.org/10.1073/pnas.0903197106

    • PubMed
    • Google Scholar
92. 1. Zhang F
    2. Hao M
    3. Jin H
    4. Yao Z
    5. Lian N
    6. Wu L
    7. Shao J
    8. Chen A
    9. Zheng S

    (2017) Canonical hedgehog signalling regulates hepatic stellate cell-mediated angiogenesis in liver fibrosis

    British Journal of Pharmacology 174:409–423.

    https://doi.org/10.1111/bph.13701

    • PubMed
    • Google Scholar

Author details

1. Nataša Pavlović

   Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

   Contribution

   Formal analysis, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

2. Carlemi Calitz

   Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

   Contribution

   Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

3. Kess Thanapirom

   Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom

   Contribution

   Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Guiseppe Mazza

   Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom

   Contribution

   Validation, Methodology

   Competing interests

   No competing interests declared

5. Krista Rombouts

   Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom

   Contribution

   Supervision, Investigation, Methodology, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

6. Pär Gerwins

   1. Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
   2. Department of Radiology, Uppsala University Hospital, Uppsala, Sweden

   Contribution

   Supervision, Funding acquisition, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

7. Femke Heindryckx

   Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   femke.heindryckx@mcb.uu.se

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1987-7676

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