TRIM family contribute to tumorigenesis, cancer development, and drug resistance

Dysregulation of ROS is a common feature of tumor cells. ROS play a vital role in modulating the tumor microenvironment, affecting the different stromal cells that provide metabolic support, blood supply, and immune responses. ROS influence tumor initiation and transformation in apparently contradictory ways, and the underlying mechanisms are complicated. Therefore, the effects of ROS-modulating therapies are difficult to predict. A better understanding of the complexity of ROS in cancer will help elucidate the potential of ROS-targeting therapies for cancer treatment [105, 106].

TRIM family members have been reported to sustain cellular homeostasis balance under oxidative stress. For example, recombinant human MG53, namely TRIM72, protected hair follicle stem cells from oxidative stress-induced apoptosis [107]. ROS can upregulate TRIM37 during HBV (Hepatitis B)-associated hepatic fibrosis which is a high risk factor for hepatocellular carcinoma [108]. Under a hypoxic conditions, TRIM14 was induced by sponging miR-191-5p in colon cancer cells, inhibiting apoptosis and promoting proliferation and invasion [109]. Some TRIMs may play opposite roles: TRIM4 could sensitize cells to hydrogen peroxide (H₂O₂) induced cell death [110]. Similarly, knockdown of TRIM8 can alleviate hypoxia/reoxygenation-induced oxidative stress [111]. Nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial cellular redox regulator, has been identified as a novel target for TRIM family proteins. In osteosarcoma, TRIM22 can interact with Nrf2 and accelerate its degradation by inducing ubiquitination dependent on its E3 ligase activity, thus activating downstream AMPK/mTOR signaling, and affecting Nrf2-mediated ROS imbalance. Moreover, TRIM22 was found to inhibit the Warburg effect in osteosarcoma cells [101]. In another study, TRIM15 was identified to promote NSCLC progression via Nrf2 stability mediated by promoting Keap1 (Kelch-like ECH associated protein 1) ubiquitination and degradation [94]. Keap1 is an E3 ubiquitin ligase, which tightly regulates the activity of Nrf2 by targeting it for ubiquitination. TRIM16 is also an integral part of the p62-Keap1-Nrf2 complex and utilizes multiple mechanisms to stabilizing Nrf2 [112]. Tumor cells also exhibit a powerful capacity, such as augmented antioxidant defense, to maintain endoplasmic reticulum (ER) homeostasis. A study found that TRIM25 is significantly induced and relieves oxidative stress upon ER stress, promoting tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation which leads to Nrf2 activation [33].

To date, only a few articles have further discussed the relationship between the regulation of cellular oxidative pressure by TRIM family proteins and tumor initiation. One study found that TRIM11 promotes tumorigenesis and is regulated by Nrf2—one of the mechanisms is reducing oxidative stress during oncogenic growth [113]. The involvement of TRIM21 in the p62-Keap1-Nrf2 axis has been reported before [114‐116]. Recently, TRIM21- knockout mice were identified to be resistant to DEN-induced hepatocarcinogenesis because the genetic ablation of TRIM21 protected cancer cells from oxidative hepatic damage [117]. Further research found that RPRD1A (regulation of nuclear pre-MRNA domain containing 1A) competitively interacts with TRIM21, affecting the upregulation of the P62-Keap1-Nrf2 pathway, and enhancing gene expression to counteract oxidative stress, maintain cancer cell survival, and promote HCC development [118].

Whereas the damaging effects of ROS can be detrimental to cell survival, the enhanced ROS driven by oncogenic perturbations is a characteristic of cancer cells as ROS drive the accumulation of oncogenic alterations that promote cancer development. Moreover, the capacity to clear oxidative substances ensures cancer cell cellular homeostasis, promoting their development. Inhibition of the way that ROS contribute to tumorigenicity and tumor development by interfering with TRIM family proteins may be a strategy, although detailed studies are needed.

A growing amount of evidence has shown that initial cancer cells undergo metabolic reprogramming including glucose metabolism, which is mediated by oncogenic drivers and by the undifferentiated character of tumor cells. The “Warburg effect”, defined as the observation that cancer cells increase the rate of glucose uptake and prefer glycolysis rather than oxidative phosphorylation even in the presence of oxygen, is widely accepted as one of the reprogramming glucose metabolism [119‐121]. Besides, high rates of glucose metabolism is also maintained in cancer cells [122]. Tumorigenesis is evidently dependent on tumor-associated metabolic reprogramming: the excessive intake of nutrients and their redistribution to metabolic pathways that are conducive to cellular tumorigenic properties, determine cellular fate and affect the tumor microenvironment, which is involved in selecting malignant phenotypes.

Several reports have shown that TRIMs participate in cancer cell reprogramming through different mechanisms. Transformed NSCLC cells maintained high glycolytic rates regardless of changing environmental mechanics by downregulating TRIM21 and by sequestering residual TRIM21 on a stress-fiber subset to retain phosphofructokinase expression and to achieve mechanical regulation of glycolysis [123]. The knockdown of TRIM23 in LUAD cells inhibited cell proliferation in vitro and in vivo, GLUT1/3 (glucose transporter type 1/3) expression, glucose uptake, and lactate and ATP production. Further research found that TRIM23 acted as an oncogene by regulating glucose metabolism via the NF-κB/GLUT1/3 axis [95]. Similarly, TRIM32 promoted the growth of gastric cancer cells through by enhancing glucose transportation by targeting GLUT1 [69]. The ubiquitous AKT has diverse downstream effects on cellular metabolism, via either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the key components. TRIM27 was reported to accelerate the glucose uptake of ESCC cells by mediating the polyubiquitination of PTEN and activating PTEN-AKT pathway [124]. To conclude, TRIM proteins are involved in tumor cell glucose metabolism reprogramming and may participate in the early stage of tumor initiation. These discoveries may shed a light on the specific component function in tumor cell “developmental pliancy” and contribute to development of other novel therapeutics.

To date, there are multiple reports that refer to the involvement of TRIM family proteins in tumorigenesis. Several studies have investigated the modulatory effects of TRIMs on oncogenic proteins or drug-induced cancer: the TRIM59 gene was upregulated in SV40 (simian vacuolating virus 40) Tag oncogene-directed transgenic and knockout mouse prostate cancer models. Further research found that the p-Ser/Thr modification of TRIM59 is correlated with tumorigenesis and that p-Tyr-TRIM59 is correlated with advanced cancer of the prostate. ShRNA-mediated knockdown of the TRIM59 caused S-phase cell cycle arrest and cell growth retardation. Moreover, the upregulation of TRIM59 gene coincided with the upregulation of genes specific to the Ras signaling pathway and bridging genes for SV40 Tag-mediated oncogenesis [125]. A study revealed that, in pancreatic ductal adenocarcinoma (PDA) models, TRIM29 accelerated pancreatic intraepithelial neoplasia (PanIN) formation and promoted the development of invasive and metastatic PDA cancer in the presence of oncogenic KRAS [126]. In contrast, TRIM67 functions as a pivotal tumor suppressor in colorectal cancer: colon-specific knockout of TRIM67 significantly accelerates azoxymethane-induced colorectal cancer in mice by activating the p53 signaling pathway [127]. A recent study found that TRIM21 was decreased in CRC and ulcerative colitis (UC)-associated cancer and negatively regulated intestinal epithelial carcinogenesis by modulating epithelial cancer cell proliferation, adhesion, tissue remodeling, angiogenesis, and proinflammatory responses [128]. Ectopic TRIM37 expression induced tumorigenicity in nontransformed cells. Further study revealed the underlying mechanism: TRIM37 could mono-ubiquitinate histone H2A, leading to the silencing of tumor suppressor genes, and facilitating the transformation from normal cells to tumor cells [129]. A recent study also confirmed this conclusion in RCC tumors. Moreover, the upregulated expression of TRIM37 could predict aggressive neoplastic phenotypes [39]. In addition, knockdown of TRIM11 suppressed the tumorigenicity of chordoma cells [130]. Because of the capability of some TRIMs to ubiquitinate misfolded proteins, we wondered whether this effect could play a role in tumorigenesis. Misfolded proteins are continually produced in cells, and are degraded mainly through autophagy and ubiquitin–proteasome systems. The diminished capability to degrade misfolded proteins is associated with a multitude of diseases, such as neurodegenerative diseases. However, the outcome of an enhanced capacity remains unclear. Interestingly, research showed that this augmented capacity was required and associated with the initiation and maintenance of malignant phenotypes. The higher degradation power in cancer cells could be attributed to enhanced proteasome activity and especially TRIM proteins. A study investigated whether TRIM11 promoted tumorigenesis through its ability to accelerate the degradation of misfolded proteins [113]. TRIM11, TRIM19, TRIM21, TRIM5, TRIM16, TRIM13, and TRIM25 also exhibited a strong capacity for misfolded protein removal. However, the specific investigations of their capability and proteasome-related oncogenesis are rare [131].

In brief, the clear recognition of TRIMs in tumor initiation, as well as the importance of TRIMs as tumor biomarkers and prognostic factors, is required to better understand cancer pathology and provide precision diagnostics and prognostic analysis for patients. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights into cancer treatments.

As p53 is one of the most crucial tumor-suppressor proteins, abnormalities such as mutations and abnormal expression levels of p53 are observed in the majority of human tumors [132]. p53 is involved in the transcription of genes, cell cycle control, DNA repair, induction of apoptosis, cell senescence and programmed death, and regulation of cellular metabolism [133, 134]. The expression of the tumor suppressor p53 is regulated at multiple levels, the disruption of which often leads to cancer. The stabilization of p53 is usually achieved by increasing the protein half-life and activating the transcriptional function of p53. MDM2 (mouse doubleminute 2 homolog) is a vital regulator of p53 by three different interconnected modes. MDM2 can inhibit the transcriptional activity of p53, alter its subcellular localization and modulate its protein stability. The MDM2-p53 hub is also vital for dictating cell cycle arrest, and tumor suppression [135, 136]. TRIM-p53 interactions have been extensively investigated. In many studies of TRIMs, TRIMs were mainly shown to regulate p53 stability and activity. Conversely, the alteration of p53 results in transcriptional regulation of TRIM proteins such as TRIM22 [137, 138], TRIM3, TRIM8, TRIM19, TRIM24, TRIM32, and TRIM67 [139]. Because of the intricate roles of TRIMs in regulation of p53 stability, we simply divide TRIMs into several subgroups: positive regulators, negative regulators, and others that play unidentified role.

The JAK/STAT pathway is known to be activated in IFN mediated antiviral activity. Owing to the important roles of JAK/STAT in cellular biology, subtle changes in their cellular concentrations could have important phenotypical consequences [174]. Constitutive activation of the JAK/STAT signaling pathway has been associated with malignancy since the 1990s. Mechanisms that cause JAK/STAT pathway activation in cancer could be activating mutations of receptors or STATs themselves and upstream oncogenes that in turn activate downstream factors or cytokine overexpression by autocrine/paracrine [175]. JAK/STAT signaling may contribute to cancer pathology by promoting inflammation, obesity, stem cells, and the premetastatic niche [176].

In physiological activities, TRIMs are closely related to the JAK/STAT signaling pathway. For example, in response to LPS, TRIM59 can recruit PIAS1 (protein inhibitor of activated STAT1) to bind with STAT1 to suppress its activation [177]. For cancer initiation and development, TRIMs may play a role through the JAK/STAT3 pathway: knockdown of TRIM66 reduced the activation of phosphorylation levels of JAK2 and STAT3 in CRC cells, and significantly inhibited cell proliferation, migration, and invasion of CRC cells [178]. TRIM8 interacts with SOCS-1 (suppressor of cytokine signaling 1), a negative regulator of STAT3 activation by the SH2 domain, and mediates its degradation, allowing the activation of JAK/STAT induced via Interferon [179]. TRIM14 also acts as a prognostic factor in PTC by promoting the ubiquitination of SOCS-1 [43]. Another study revealed that TRIM14 acts as a positive regulator of the SPHK1/STAT3 signaling pathway, promoting CRC cell migration and invasion [180]. Several TRIMs, such as TRIM27, TRIM29, and TRIM52, have also been reported to mediate the overactivation of STAT3 and induce the expression of downstream target genes, such as MMP-2 (Matrix metalloproteinases 2), MMP-9, and VEGF (vascular endothelial growth factor), thus promoting cancer cell migration and invasion [180‐183]. In contrast, TRIM16 is involved in the JAK/STAT pathway as a negative factor in miR-135-regulated NSCLC sensitivity to gefitinib [184].

The antitumor immune surveillance processes orchestrated by the activity of immune cells and immune-regulatory factors are chiefly driven by JAK/STAT signaling [185]. Interestingly, TRIMs have also been widely reported to be associated with the innate immune response. TRIMs regulate the IFN-I mediated innate immune response, which plays a vital role in antiviral and antitumor responses [186]. The contributions of TRIMs to the dysregulation of the JAK/STAT pathway in cancer cells have been illustrated in several studies above. The connection between TRIMs, and JAK/STAT-associated antitumor immune surveillance has not been established. Therefore, the new research topic could be studied: TRIM-mediated antitumor immune response.

As a consequence of extensive downstream factors and complicated crosstalk with other signaling pathways, PI3K/AKT is involved in almost all cellular processes. Thus, anomalous activation is frequently detected in a range of tumor types. To date, more than 50 compounds that target key components of this signaling network have been tested in clinical trials involving patients with various cancers, indicating its importance in oncology [187].

The oncogenic functions of TRIM11 in cancer have been investigated in cholangiocarcinoma, HCC [188], lung cancer [92], ovarian cancer [189], and cervical cancer [190]. Downregulation of TRIM11 decreases the phosphorylation levels of p-PI3K and p-AKT. Furthermore, TRIM11 can facilitate the K48-linked ubiquitination-mediated degradation of PHLPP1 (PH domain and leucine rich repeat protein phosphatase 1), which suppresses AKT by dephosphorylation, activating the AKT signaling pathway [30, 130]. In addition, TRIM11 promoted glycolysis by modulating AKT/GLUT1 in breast cancer cells [191]. Overexpression of TRIM46 also increases glycolysis in LUAD cells and the cell proliferation rate, and promotes xenograft growth by increasing the ubiquitination of PHLPP2 and upregulating of p-AKT in lung cancer [97]. Downregulation of TRIM59 restricts the PI3K/AKT/mTOR signaling pathway [192]. TRIM44 also promotes the AKT pathway and affectes its downstream mTOR signaling pathway, modulating the EMT process [44, 193]. TRIM26 exerts an oncogenic effect in bladder cancer via AKT/GSK3β/β-catenin [194]. TRIM14 knockdown increases the protein levels of PTEN, which subsequently inactivates AKT pathways in melanoma [195] and colorectal cancer [196]. TRIM14 overexpression resultes in lower proliferation rates and reduced apoptosis in AML [197]. In addition, similar effects were observed in osteosarcoma [198] and gastric cancer [199]. TRIM37 was also identified as a modulator of the ubiquitination of PTEN, thereby activating the AKT/GSK-3β-β-catenin axis in pancreatic cancer [59, 200]. The TRIM27 expression level can be reduced by an AKT inhibitor [201]. TRIM27 functions as a pro-proliferative factor, and participates in energy metabolism by activating the PI3K/AKT pathway in esophageal squamous cell carcinoma [124], and cell cycle arrest, and apoptosis in ovarian cancer [202] and facilitates the invasion and metastasis of colorectal cancer [53]. TRIM59 was proven to enhance PC progression by activating the PI3K/AKT/mTOR-glycolysis signaling pathway [61], CRC [203], breast cancer [88], and cholangiocarcinoma progression [192]. Some TRIMs may exert their role by directly affecting AKT and downstream signaling pathways or being modulated by AKT. A previous study demonstrated the involvement of TRIM24 in the regulation of the AKT signaling pathway in bladder cancer [204]. A later study proved that TRIM24 could directly activate the PIK3CA gene, which encodes the catalytic subunit of PI3Ks in glioma [205]. To date, two TRIM family members, TRIM13 [158] and TRIM21 [206] have been identified to directly mediate the proteasomal degradation of AKT. TRIM21 can be negatively regulated by AKT [207]. In addition, TRIM31 [42, 208], TRIM32 [69], and TRIM47 [209] were reported to play a role in the AKT signaling pathway in cancer.

The clinical efficacy of PI3K inhibitors has been challenged by adverse clinical effects such as hyperglycemia and tumor resistance. Targeting AKT has great therapeutic potential but may also be limited owing to the extensive downstream substrates and complicated crosstalk with other signaling pathway networks [210]. Clarifying the relationship between TRIMs and PI3K/AKT may provide a new perspective on cancer therapy. Although the connection with multiple TRIM family proteins has been identified, studies have not fully elucidated the specific way that TRIMs affect the PI3K/AKT signaling pathway.

The transforming growth factor β (TGF-β) signaling pathway controls the homeostasis of cell and tissue development. The transduction process of the TGF-β/SMAD pathway usually includes the initial binding of a TGF-β family member to its type II receptor in concert with a type I receptor. Then, the complex activates the type I receptor, and subsequently phosphorylates a receptor-regulated SMAD2/3, allowing it to associate with SMAD4 and to move into the nucleus to bind to specific enhancers in target genes activating transcription [211]. The altered production of, or responsiveness to, TGF-β changes cancer cell behavior. Interestingly, the TGF-β signaling pathway is now considered a double-edged sword in which TGF-β exerts both positive and negative influences on cancer development.

The connection between TRIMs and TGF-β has been identified in several articles. Endoglin is an auxiliary component of the TGF-β receptor and has been shown to have a binding relationship with TRIM21 in human endothelial cells, although further regulatory mechanisms have not been revealed [212]. TRIM33 functions in the TGF-β signaling pathway by interacting with SMAD2/3 and ubiquitinating SMAD4 [213, 214]. TRIM47 also physically interacts with SMAD4, increasing its ubiquitination and degradation [215]. TRIM37 promotes RCC cell EMT and malignant progression through TGF-β signaling activation, as a consequence of TRIM37 mediated H2A ubiquitination modification [39]. TRIM59 was found to downregulate the protein expression of p-SMAD2 and thus inhibit the activity of the TGF-β signaling pathway [216‐218]. Likewise, in bladder cancer, silencing TRIM59 inhibites the TGF-β/SMAD2/3 signaling pathway and affectes the downstream EMT process [217]. TRIM62 promotes the ubiquitination of SMAD3, acting as a negative regulator in the TGF-β pathway. Thus, it also influences the downstream targets of AMAD2-SNAL1/2 and the EMT process [219]. The downregulation of TRIM52 significantly induces SMAD2/3 dephosphorylation in hepatocellular carcinoma cells [160]. Research also revealed that TRIM66 [220], TRIM25 [221‐223] and TRIM32 are involved in TGF-β signaling pathways to promote cancer cell proliferation and invasion [68].

TRIM family proteins may positively or negatively regulate the TGF-β signaling pathway in cancer cells. However, due to the complexity of the TGF-β signaling pathway in regulating cancer cell activity. TRIMs may act as either tumor suppressors or promoters depending on the regulatory mechanisms and different cancer cell types. Therefore, further analyses are required to determine its roles in cancer initiation and progression.

The Wnt signal transduction cascade is a key driver of various tissue stem cells and the main regulator of development phases. Hence, mutated or dysregulated Wnt pathway components cause many growth-related pathologies and tumorigenesis, tumor progression and resistance [224]. To date, only a few TRIM family proteins have been associated with the abnormalities in the Wnt/β-catenin signaling pathway.

Glycogen synthase kinase 3β (GSK-3β) is a crucial upstream suppressor of β-catenin. Research has found that GSK-3β mediates the phosphorylation of β-catenin, promoting its ubiquitination [225]. Disheveled (Dvl), is a cytoplasmic protein that is activated when Wnt ligands bind to the coreceptor. Subsequently, activated Dvl attaches to the Axin/GSK-3β complex and antagonizes GSK-3β-dependent phosphorylation of β-catenin. TRIM29 can interact with Dvl-2 to stabilize β-catenin and exert oncogenic functions in pancreatic cancer [226, 227]. In addition, knockdown of TRIM29 enhances GSK-3β protein expression and inhibited the expression of β-catenin and c-myc, thereby activating the β-catenin signaling pathway in cervical cancer [228]. In colorectal cancer, TRIM29 induces the activation of the Wnt/β-catenin signaling pathway via upregulation of CD44 expression [126, 229, 230]. TRIM26 exerts an oncogenic role in bladder cancer through the regulation of cell proliferation, migration, and invasion via the AKT/GSK3β/β-catenin pathway [231]. TRIM32 could significantly enhance the expression of β-catenin and downstream target mRNAs in GC [232]. The latter study showed that TRIM32 ubiquitinates Axin1 (axis inhibition protein 1), which is a robust negative regulator of regulating Wnt/β-catenin signaling activity in rat nucleus pulposus cells [233]. TRIM46 was also found to act as a promoter in the ubiquitination and proteasomal degradation of Axin1 protein in HK-2 cells [234]. Silencing TRIM44 in PTC inhibited the proliferation, migration, and invasion of cancer cells by suppressing of the Wnt/β-catenin signaling pathway, indicating its oncogenic function [193]. TRIM31 promotes AML cell proliferation and sensitivity to daunorubicin in AML cells through the Wnt/β-catenin signaling pathway [235]. TRIM59 also has a positive role in the Wnt/β-catenin signaling pathway in neuroblastoma [236]. In contrast, TRIM58 showed a tumor-suppressive role by inactivating of β-catenin signaling via ubiquitination in gastric cancer [237]. Regarding tumor resistance, TRIM11-mediated drug resistance depends on activating β-catenin/ABCC9 signaling by facilitating the degradation of Daple in NPC [46]. Moreover, TRIM15 [238], TRIM24 [32], TRIM37 [239], and TRIM47 [240] were demonstrated to positively modulate β-catenin pathways.

In summary, based on all these studies, the majority of TRIM family proteins appear to act as oncogenic factors when they activate the Wnt/β-catenin signaling pathway. However, whether the aberrant Wnt/β-catenin signaling pathway regulated by TRIMs contributes to cancer stem cell formation and development is still unknown. Nevertheless, the additional regulatory mechanisms that have been identified for the control of β-catenin help us better understand why the aberrant Wnt/β-catenin signaling pathway exerts crucial roles in cancer stem cell renewal, cell proliferation, and differentiation.

The importance of NF-κB signaling in the cancer field has been understood for decades. It has become increasingly clear that the anomalies in the NF-κB signaling pathway are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy [241, 242]. Moreover, many reports have suggested that TRIM family proteins are recruited at different steps of TNF-α-induced activation of the NF-κB signaling pathway and form a feedback loop in the innate and adaptive immune pathways [243].

In osteosarcoma, TRIM10 contributes to cisplatin resistance by increasing the nuclear levels of p65, thereby activating canonical NF-κB signaling [244]. TRIM8 could activate the NF-κB signaling pathway in two ways: promoting the cytoplasmic degradation of PIAS3 (protein inhibitor of activated STAT3), inhibiting its binding with p65 [245]; and mediating the Lys63-linked polyubiquitination of TAK1 (a serine/threonine kinase essential for TNFα- and IL-β-induced NF-κB activation) at Lys158, activating downstream NF-κB [246]. Interestingly, the atypical TRIM family protein TRIM44 which lacks the RING finger domain, was revealed to promote breast cancer cell proliferation and migration by enhancing NF-κB signaling [84]. Further study revealed that TRIM44 knockdown substantially attenuated the TNFα-dependent phosphorylation of the p65 subunit of NF-κB and IκBα [85]. IκBα, as an inhibitor of NF-κB, can interact with TRIM27 [34] and TRIM22 [247] to achieve ubiquitination-mediated degradation, leading to NF-κB activation. Further research found that TRIM22 accelerated IκBα degradation by inducing K48-linked ubiquitination. TRIM22 also forms a complex with the NF-κB upstream regulator IKKγ and promotes K63-linked ubiquitination, which leads to the phosphorylation of both IKKα/β and IκBα [248]. A negative regulator of the NF-κB signaling pathway-, TRIM67, was demonstrated to competitively bind β-TrCP (β-transducin repeat-containing protein) to IκBα, resulting in inhibition of β-TrCP-mediated degradation of IκBα, which finally resulted in inhibition of TNFα-triggered NF-κB activation [249]. In LUAD, elevated TRIM23 expression is positively correlated with expression of the NF-κB [95]. A link between TRIM37 and the NF-κB pathway was described in the context of NSCLC where NF-κB is constitutively activated. Related research has demonstrated that TRIM37 induces the K63 polyubiquitination of TRAF2 (TNF receptor associated factor 2), a significant activator of NF-κB signaling [250]. PKC-ε (protein kinase C-ε), which also acts as an NF-κB-activating protein kinase, is directly associated with TRIM47 to achieve lysine 27-linked polyubiquitination of PKC-ε, enhancing NF-κB signaling, which in turn up-regulates TRIM47 [86]. In addition, TRIM46 acts as an oncogene in OS by interacting with and ubiquitinating PPARα (peroxisome proliferator-activated receptor α), leading to the activation of the NF-κB signaling pathway [251]. Activation of the NF-κB pathway is also positively correlated with TRIM52 [252], TRIM14 [253], and TRIM31 [254] and promotes cancer development in cancers. In NSCLC, TRIM13 behaves as a tumor suppressor through by negatively regulating the NF-κB pathway [255].

The relationship between TRIM family proteins and NF-κB signaling transduction has been investigated mainly in immune response research. Further studies are needed to help clarify the role of TRIM-mediated regulation of NF-κB in different pathological conditions, especially in antitumor immunity and tumor resistance.

The Notch, AMPK, MAPK, and YAP signaling pathways have also been reported to play vital roles in cancer. Knockdown a crucial coactivator of Notch receptors and signal transmission and function, decreases the expression of TRIM13, TRIM32, TRIM44, and TRIM59 especially in T-ALL [94]. The activation of MAPK enhances TRIM2 protein levels and affectes its binding with Bim, resulting in reduced Bim in tamoxifen-resistant breast cancer cells [256]. TRIM28 also regulates the degradation of AMPK [257]. TRIM22 inhibites osteosarcoma progression by promoting proteasomal degradation of NRF2 independent of KEAP1, thereby activating AMPK/mTOR/autophagy signaling that led to autophagic osteosarcoma cell death [101]. In colorectal cancer, TRIM24 directly interactes with the YAP promoter at the 983 to 734 site and activated YAP transcription, ultimately enhancing the proliferation of cells [258]. In breast cancer, TRIM6 was demonstrated to interact with STUB1 (STIP1 homology and U-box containing protein 1) and mediate its degradation thereby promoting YAP1 signaling [259]. TRIM31 promotes the malignant behaviors of HCC cells by directly promoting the E3 ligase-mediated K48-linked ubiquitination and degradation of upstream suppressors of the mTORC1 pathway [35].

In summary, the TRIM family and the involved signaling pathway do not have a simple one-way relationship. In fact, the same TRIM molecule may directly or indirectly participate in multiple signaling pathways, acting both as an oncogene and a tumor suppressor gene. Additionally, one signaling pathway may require multiple molecules to precisely regulate each step of the cell life cycle. Understanding the regulatory network of the TRIM family is the basis for developing related therapies.

EMT is a reversible cellular programmer that transiently places epithelial cells into mesenchymal cell states. During this process, epithelial cells progressively lose their cobblestone epithelial appearance in monolayer cultures to adopt a spindle-shaped, mesenchymal morphology [260, 261]. EMT was found to be activated during cancer progression and attributed to cancer resistance. TRIM directly or indirectly modulates EMT through various signaling pathways. For example, TRIM50 acts as a tumor suppressor in HCC cells by directly targeting snail and reversing EMT [28]. TRIM50 also inhibits pancreatic cancer progression and reverses EMT [56]. TRIM24 [32] and TRIM58 [50] are involved in EMT by modulating snail, slug, and vimentin, and E-cadherin. The effect of TRIM11 in promoting the EMT process has been confirmed in hepatocellular cancer [188], gastric cancer [262], and lung cancer [92]. TRIM65 modulates cytoskeleton rearrangement and induces UCB cell EMT by the ubiquitination of Annexin A2, ultimately leading to enhanced invasiveness of UCB cells [41]. ZEB2 (zinc finger E-box binding homeobox 2), a transcription factor involved in EMT, is also a downstream target of TRIM14. The overexpression of TRIM14 promotes EMT through ZEB2 [76]. Interestingly, knockdown of TRIM16 accelerates EMT by inhibiting ZEB2 expression, which in turn inhibits the transcription of E-cadherin [31]. TRIM16 was also proven to suppress the sonic hedgehog signaling pathway as well as the EMT process in ovarian cancer [263]. TRIM62 functions as a significant regulator of apical-basal polarity and acinar morphogenesis, as well as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven EMT [219]. TRIM29 also induced an EMT phenotype in PDA by the Wnt/β-catenin pathway [126]. Apart from the main pathway mentioned above, TRIM21 [128], TRIM27 [53], and TRIM66 [178], were also related to the EMT process. Nevertheless, in-depth research on the detailed mechanisms is needed, and the studies above provide new insights into the progression of cancer.

The CSCs theory is a classic cancer resistance mechanism, which suggests that CSCs are inherently resistant to some cancer therapies [264]. Within a heterogeneous tumor mass, only approximately 0.05–3% of cells are suspected to be CSCs. Interestingly, CSCs, cancer cells, and normal stem cells share a variety of cytochemical properties. For example, inhibition of the redox system for ROS production and a high drug efflux property, which contribute to resistance to anticancer drugs. CSCs can also undergo EMT transition to better migrate to the surrounding tissues [265]. With the concept of CSCs evolving, researchers have found that the abnormalities in TRIM family activities function in the acquisition and maintenance of the cancer stem cell phenotype. TRIM29 modulates the CSC-like features of PDAC [266]. A recent study identified TRIM29 maintenance of CSCs-like characteristics in ovarian cancer through facilitated SETBP1 (SET Binding Protein 1) transcriptional activation and the downstream SET axis [267]. TRIM37 was also able to promote PC stem cell-like traits [59]. TRIM6, TRIM11, TRIM14, TRIM19, TRIM24, TRIM25, TRIM27, TRIM28, and TRIM71 act as positive regulators in the acquisition and maintenance of CSCs. TRIM16, TRIM21, and TRIM32 act as negative regulators [268]. Another study found that TRIM16, TRIM32, TRIM24, TRIM8, TRIM27, TRIM11, and PML are associated with cancer stem cells and the clinical prognosis of RCC, and affect tumor progression [269]. The DNA damage and repair (DDR) process determines the fate of cell death and survival under endogenous and exogenous sources of pressure. In some cases, DNA damage is not addressed properly, leading to genome instability, which makes the cell susceptible to malignant transformation. Many proteins are involved in this signaling cascade including TRIMs. A subfamily of the TRIM-transcriptional intermediary factor 1 (TIF1) family consists of TRIM24, TRIM48, TRIM33, and TRIM66 [12]. The TIF1 family plays an important role in DNA repair and mitosis, transcription, cell differentiation and cell cycle regulation, and immunity. The TIF1 family members are often dysregulated in hepatocellular carcinoma [270], manifested as altered gene expression, deletions, translocations, or loss-of-function mutations [12]. Interestingly, the TIF1 family exhibits distinct expression patterns in stem cell-like tumors. In contrast to the rest of the TIF1 members, only TRIM28-associated gene expression profiles are strongly enriched with stemness markers regardless of the tumor type. Moreover, TRIM28 is highly expressed in higher-grade tumors with stem cell-like traits [271]. Overall, we still need more evidence to explore and support TIF1 function in maintaining genome stability during DNA damage in cancer stem cells. To date, CSCs developing chemoresistance during chemotherapy regimens remain the hardest obstacle to overcome for cancer treatment, and TRIMs may be potential targets.

TRIM family is involved in chemoresistance in many cancers. Since substantial TRIM family proteins mediate the chemotherapy response and most of them function as a promoter to chemoresistance, there may be a new promising therapeutic target in the future. Table 2 summarize the roles of TRIM family members in mediating cancer cells to chemotherapy and mechanisms.

In addition to chemotherapy, targeted cancer therapy mainly consists of two approaches: antibodies and small molecules. Most of them are highly selective with fewer side-effects than chemotherapy. Although many drugs have achieved success in clinical trials, drug resistance remains a challenge. Several studies have identified the role of TRIMs in targeted therapy: The sensitivity of NCSLC cells to gefitinib is mediated by TRIM16, as the suppression of miR-135 could improve sensitivity to gefitinib by upregulation of TRIM16 [184]. A study found that apatinib-reduced gastric cancer cell proliferation was significantly abolished by TRIM21 knockdown; in turn, promoting TRIM21 expression further improved the sensitivity of gastric cancer cells to apatinib [63]. In addition, the sorafenib resistance in HCC cells could be mediated by TRIM37 overexpression [36]. EBBP (estrogen-responsive b box brotein) is also a member of the TRIM protein family. EBBP acts to derepress the transcription of RARb2 (retinoic acid receptor β2) and CYP26A1 (cytochrome P450 family 26 subfamily A member 1), by modifying histone acetylation in retinoid-resistant cancer cells [281].

In hormone-driven cancers such as prostate cancer, ligand-deprivation therapy is used as a standard treatment. Sometimes it fails when tumors evolve to activate androgen receptor signaling. Several TRIMs are involved in steroid hormone regulation [282]. TRIM24 was deemed a major effector of “AR reprogramming” [283] and contributed to castration-resistant prostate cancer (CRPC) [283]. In ER⁺ breast cancer, TRIM39 [83] and TRIM29 knockdown significantly suppresse ER⁺ breast cancer cell proliferation [79]. In addition, in ER⁺ breast cancer, TRIM3 promotes SUMO modification of estrogen receptor 1(ESR1) and activated the ER signaling pathway. TRIM3 also confers tamoxifen resistance [82]. TRIM2 is also involved in tamoxifen resistance through binding with Bim [256]. TRIM47 facilitates endocrine therapy resistance in breast cancer by affecting the NF-κB signaling pathway [86]. In addition to these findings, the overexpression of TRIM29 was shown to mediate the resistance to ionizing radiation (IR) [154]. A recent study revealed that the TRIM29 and TRIM37 genes were involved in the cell response to radiation and could function as predictive biomarkers for radiation sensitivity in normal and tumor cell lines [284].

The therapeutic resistance of cancer is an evolving paradigm as novel regimens merge from chemotherapy, and target therapy to immune therapy. By virtue of advanced screening techniques and biological approaches, novel mechanisms of drug resistance and molecular signatures and genotypes have been gradually uncovered to help us better predict tumor responses and resolve resistance.