nach oben

Clinical and Translational Oncology

Erschienen in:

18.05.2020 | Research Article

FAM83H overexpression predicts worse prognosis and correlates with less CD8⁺ T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in pancreatic cancer

verfasst von: H. Zhuang, C. Zhang, B. Hou

Erschienen in: Clinical and Translational Oncology | Ausgabe 12/2020

Einloggen, um Zugang zu erhalten

Abstract

Background

Family with sequence similarity 83 members H (FAM83H) is one member of Family with sequence similarity 83 (FAM83) family, which possess oncogenic properties in several types of cancer. However, the potential function of FAM83H in pancreatic cancer (PC) still remain unknown.

Aim

This study aims to explore the role of FAM83H during pancreatic carcinogenesis and the regulation of immune infiltration in PC.

Methods

In the current study, the clinical significance and potential biological of FAM83H were evaluated by bioinformatics analysis. Possible associations between FAM83H expression and tumor immunity were analyzed using ESTIMATE algorithm and single-sample gene set enrichment analysis (ssGSEA).

Results

FAM83H expression was significantly upregulated in tumor tissues, and positively associated with higher histologic grade, tumor recurrence, and worse prognosis. FAM83H overexpression is notably associated with KRAS activation. And functional enrichment analysis demonstrated that FAM83H may be involved in positive regulation of cell proliferation and migration, Ras protein signal transduction, regulation of cell–matrix adhesion, epithelial to mesenchymal transition (EMT), TGF-β receptor signaling in EMT, and activated NOTCH transmits signal to the nucleus. ESTIMATE algorithm and ssGSEA demonstrated that FAM83H overexpression suppressed the infiltration and antitumor activity of tumor-infiltrating lymphocytes (TILs), especially for CD8⁺ T cells. Besides, FAM83H overexpression significantly correlated with low expression of TIL-related gene markers (e.g. CD8A, CD8B, CD2, CD3D, and CD3E).

Conclusion

The study suggests that FAM83H overexpression predicts poor prognosis and correlates with less CD8⁺ T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in PC.

Kamisawa T, Wood LD, Itoi T, et al. Pancreatic cancer. Lancet. 2016;388(10039):73–85.PubMedCrossRef

Mishra NK, Southekal S, Guda C. Survival analysis of multi-omics data identifies potential prognostic markers of pancreatic ductal adenocarcinoma. Front Genet. 2019;10:624.PubMedPubMedCentralCrossRef

Bazhin AV, Shevchenko I, Umansky V, et al. Two immune faces of pancreatic adenocarcinoma: possible implication for immunotherapy. Cancer Immunol Immunother. 2014;63(1):59–655.PubMedCrossRef

Cervello M, Emma MR, Augello G, et al. New landscapes and horizons in hepatocellular carcinoma therapy. Aging (Albany NY). 2020;12:3053.PubMedPubMedCentralCrossRef

Schouwenburg MG, Suijkerbuijk KPM, Koornstra RHT, et al. Switching to immune checkpoint inhibitors upon response to targeted therapy; the road to long-term survival in advanced melanoma patients with highly elevated serum LDH? Cancers (Basel). 2019;11(12):1940.CrossRef

Balachandran VP, Beatty GL, Dougan SK. Broadening the impact of immunotherapy to pancreatic cancer: challenges and opportunities. Gastroenterology. 2019;156(7):2056–72.PubMedCrossRef

Cai L, Luo D, Yao B, et al. Systematic analysis of gene expression in lung adenocarcinoma and squamous cell carcinoma with a case study of FAM83A and FAM83B. Cancers (Basel). 2019;11(6):886.CrossRef

Cipriano R, Miskimen KL, Bryson BL, et al. Conserved oncogenic behavior of the FAM83 family regulates MAPK signaling in human cancer. Mol Cancer Res. 2014;12(8):1156–65.PubMedPubMedCentralCrossRef

Kuga T, Sasaki M, Mikami T, et al. FAM83H and casein kinase I regulate the organization of the keratin cytoskeleton and formation of desmosomes. Sci Rep. 2016;6:26557.PubMedPubMedCentralCrossRef

10.

Lee MJ, Lee SK, Lee KE, et al. Expression patterns of the Fam83h gene during murine tooth development. Arch Oral Biol. 2009;54(9):846–50.PubMedCrossRef

11.

Chen C, Li HF, Hu YJ, et al. Family with sequence similarity 83 member H promotes the viability and metastasis of cervical cancer cells and indicates a poor prognosis. Yonsei Med J. 2019;60(7):611–8.PubMedPubMedCentralCrossRef

12.

Kim KM, Hussein UK, Park SH, et al. FAM83H is involved in stabilization of beta-catenin and progression of osteosarcomas. J Exp Clin Cancer Res. 2019;38(1):267.PubMedPubMedCentralCrossRef

13.

Kuga T, Kume H, Kawasaki N, et al. A novel mechanism of keratin cytoskeleton organization through casein kinase Ialpha and FAM83H in colorectal cancer. J Cell Sci. 2013;126(Pt 20):4721–31.PubMed

14.

Nalla AK, Williams TF, Collins CP, et al. Lentiviral vector-mediated insertional mutagenesis screen identifies genes that influence androgen independent prostate cancer progression and predict clinical outcome. Mol Carcinog. 2016;55(11):1761–71.PubMedCrossRef

15.

Kim KM, Park SH, Bae JS, et al. FAM83H is involved in the progression of hepatocellular carcinoma and is regulated by MYC. Sci Rep. 2017;7(1):3274.PubMedPubMedCentralCrossRef

16.

Kim KM, Hussein UK, Bae JS, et al. The expression patterns of FAM83H and PANX2 are associated with shorter survival of clear cell renal cell carcinoma patients. Front Oncol. 2019;9:14.PubMedPubMedCentralCrossRef

17.

Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.CrossRefPubMed

18.

Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 2013;14:7.CrossRef

19.

Yoshihara K, Shahmoradgoli M, Martinez E, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.PubMedCrossRef

20.

Bindea G, Mlecnik B, Tosolini M, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 2013;39(4):782–95.PubMedCrossRef

21.

Van Sciver RE, Lee MP, Lee CD, et al. A new strategy to control and eradicate “undruggable” oncogenic K-RAS-driven pancreatic cancer: molecular insights and core principles learned from developmental and evolutionary biology. Cancers (Basel). 2018;10(5):142.PubMedCentralCrossRef

22.

Cullis J, Das S, Bar-Sagi D. Kras and tumor immunity: friend or foe? Cold Spring Harb Perspect Med. 2018;8(9):a031849.PubMedPubMedCentralCrossRef

23.

Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte–macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell. 2012;21(6):822–35.PubMedPubMedCentralCrossRef

24.

El-Jawhari JJ, El-Sherbiny YM, Scott GB, et al. Blocking oncogenic RAS enhances tumour cell surface MHC class I expression but does not alter susceptibility to cytotoxic lymphocytes. Mol Immunol. 2014;58(2):160–8.PubMedCrossRef

25.

Cui LH, Li CX, Zhuo YZ, et al. Saikosaponin d ameliorates pancreatic fibrosis by inhibiting autophagy of pancreatic stellate cells via PI3K/Akt/mTOR pathway. Chem Biol Interact. 2019;300:18–26.PubMedCrossRef

26.

Brown NF, Marshall JF. Integrin-mediated TGFbeta activation modulates the tumour microenvironment. Cancers (Basel). 2019;11(9):1221.PubMedCentralCrossRef

27.

Jiang Y, Zhan H. Communication between EMT and PD-L1 signaling: new insights into tumor immune evasion. Cancer Lett. 2020;468:72–81.PubMedCrossRef

28.

Neuzillet C, Tijeras-Raballand A, Cohen R, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.PubMedCrossRef

29.

Du X, Zhang S, Cheng Z, et al. Effect of Notch1 signaling pathway activation on pancreatic cancer cell proliferation in vitro. Nan Fang Yi Ke Da Xue Xue Bao. 2013;33(10):1494–8.PubMed

30.

Maniati E, Bossard M, Cook N, et al. Crosstalk between the canonical NF-kappaB and Notch signaling pathways inhibits Ppargamma expression and promotes pancreatic cancer progression in mice. J Clin Investig. 2011;121(12):4685–99.PubMedCrossRefPubMedCentral

31.

Villegas SN, Gombos R, Garcia-Lopez L, et al. PI3K/Akt cooperates with oncogenic notch by inducing nitric oxide-dependent inflammation. Cell Rep. 2018;22(10):2541–9.PubMedCrossRef

32.

Mu GG, Zhang LL, Li HY, et al. Thymoquinone pretreatment overcomes the insensitivity and potentiates the antitumor effect of gemcitabine through abrogation of Notch1, PI3K/Akt/mTOR regulated signaling pathways in pancreatic cancer. Dig Dis Sci. 2015;60(4):1067–80.PubMedCrossRef

33.

Sierra RA, Thevenot P, Raber PL, et al. Rescue of notch-1 signaling in antigen-specific CD8⁺ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol Res. 2014;2(8):800–11.PubMedPubMedCentralCrossRef

Titel: FAM83H overexpression predicts worse prognosis and correlates with less CD8+ T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in pancreatic cancer
verfasst von: H. Zhuang
C. Zhang
B. Hou
Publikationsdatum: 18.05.2020
Verlag: Springer International Publishing
Erschienen in: Clinical and Translational Oncology / Ausgabe 12/2020
Print ISSN: 1699-048X
Elektronische ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-020-02365-z

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

FAM83H overexpression predicts worse prognosis and correlates with less CD8⁺ T cells infiltration and Ras-PI3K-Akt-mTOR signaling pathway in pancreatic cancer

Abstract

Background

Aim

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Background

Aim

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 12/2020

Clinical activity of brigatinib in ROS1-rearranged non-small cell lung cancer

A population perspective on the use of external beam radiotherapy in Catalonia, Spain

Research progress of tumor microenvironment and tumor-associated macrophages

Dynamic evaluation of neutrophil-to-lymphocyte ratio as prognostic factor in stage III non-small cell lung cancer treated with chemoradiotherapy

Potential roles of lymphovascular space invasion based on tumor characteristics provide important prognostic information in T1 tumors with ER and HER2 positive breast cancer

Potential biomarkers for early detection of pancreatic ductal adenocarcinoma

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie