Interferon-Induced Transmembrane Protein 3 Expression Upregulation Is Involved in Progression of Hepatocellular Carcinoma

Overview

Journal Biomed Res Int

Publisher Wiley

Specialties Biomedical Engineering
Biotechnology
General Medicine

Date 2021 Apr 5

PMID 33816616

Citations 7

Authors

Yuli Hou

Shanshan Wang

Mengdan Gao

Jing Chang

Jianping Sun

Ling Qin

Ang Li

Fudong Lv

Jinli Lou

Yonghong Zhang

Yan Zhao

Affiliations

Soon will be listed here.

Abstract

Purpose: Interferon-induced transmembrane protein 3 (IFITM3) is a key signaling molecule regulating cell growth in some tumors, but its function and mechanism in hepatocellular carcinoma (HCC) remain unknown. Our study investigated the relationship between the expression of IFITM3 and HCC development. . IFITM3 expression was identified via multiple gene expression databases and investigated in HCC tissue samples. Then, PLC/PRF/5 cells were transfected with lentivirus to knock down and overexpress the expression of IFITM3. IFITM3 expression, cell proliferation, and migration were detected by qRT-PCR, western blotting, QuantiGene Plex 2.0 assay, immunohistochemistry, CCK-8, and wound healing tests. RNA-seq technology identified the PI3K/AKT/mTOR pathway as an IFITM3-related signaling pathway for investigation.

Results: IFITM3 expression was higher in HCC tissues than in adjacent normal tissues, and the level of IFITM3 was higher in HCC tissues with low differentiation and metastatic potential than in those with high/medium differentiation and without metastatic potential. A higher RNA level of IFITM3 was found in samples with IFITM3 rs12252-CC genotype rather than the TT genotype. Knockdown of IFITM3 in PLC/PRF/5 cells inhibited cell proliferation and migration, blocked the expression of the PI3K/AKT/mTOR signaling pathway, and decreased the expression of vimentin. The results were opposite with the overexpression of IFITM3.

Conclusion: Upregulation of IFITM3 plays a role in the development of HCC. Possibly through regulating HCC cell proliferation and migration, these effects are associated with the PI3K/AKT/mTOR signaling pathway. Upregulation of IFITM3 is also associated with the IFITM3 rs12252-CC genotype.

Citing Articles

Research Progress into the Biological Functions of IFITM3.

Xie Q, Wang L, Liao X, Huang B, Luo C, Liao G Viruses. 2024; 16(10).

PMID: 39459876 PMC: 11512382. DOI: 10.3390/v16101543.

Role of interferon-induced transmembrane protein family in cancer progression: a special focus on pancreatic cancer.

Wang P, Pan Y, Zhang Y, Chen C, Hu J, Wang X Med Oncol. 2024; 41(4):85.

PMID: 38472606 DOI: 10.1007/s12032-024-02308-6.

Interferon-induced transmembrane protein 3 in hepatocellular carcinoma patients.

Bondok R, Barakat L, Elsergany A, Mahsoub N, Ghattas M BMC Cancer. 2023; 23(1):584.

PMID: 37353775 PMC: 10290370. DOI: 10.1186/s12885-023-11071-2.

Taurodeoxycholic acid-YAP1 upregulates OTX1 in promoting gallbladder cancer malignancy through IFITM3-dependent AKT activation.

Yang R, Yang L, Long M, Wu F, Shi Y, Xia R Oncogene. 2023; 42(18):1466-1477.

PMID: 36928361 DOI: 10.1038/s41388-023-02660-3.

IFITM protein regulation and functions: Far beyond the fight against viruses.

Friedlova N, Zavadil Kokas F, Hupp T, Vojtesek B, Nekulova M Front Immunol. 2022; 13:1042368.

PMID: 36466909 PMC: 9716219. DOI: 10.3389/fimmu.2022.1042368.

References

Mikedis M, Downs K . Widespread but tissue-specific patterns of interferon-induced transmembrane protein 3 (IFITM3, FRAGILIS, MIL-1) in the mouse gastrula. Gene Expr Patterns. 2013; 13(7):225-39. PMC: 3704145. DOI: 10.1016/j.gep.2013.04.003. View

Xu M, Liu Z, Wang C, Yao B, Zheng X . EDG2 enhanced the progression of hepatocellular carcinoma by LPA/PI3K/AKT/ mTOR signaling. Oncotarget. 2017; 8(39):66154-66168. PMC: 5630400. DOI: 10.18632/oncotarget.19825. View

Min J, Feng Q, Liao W, Liang Y, Gong C, Li E . IFITM3 promotes hepatocellular carcinoma invasion and metastasis by regulating MMP9 through p38/MAPK signaling. FEBS Open Bio. 2018; 8(8):1299-1311. PMC: 6070650. DOI: 10.1002/2211-5463.12479. View

Williams D, Wu W, Grotefend C, Radic V, Chung C, Chung Y . IFITM3 polymorphism rs12252-C restricts influenza A viruses. PLoS One. 2014; 9(10):e110096. PMC: 4196997. DOI: 10.1371/journal.pone.0110096. View

Dai F, Chen Y, Huang L, Wang J, Zhang T, Li J . A novel synthetic small molecule YH-306 suppresses colorectal tumour growth and metastasis via FAK pathway. J Cell Mol Med. 2014; 19(2):383-95. PMC: 4407606. DOI: 10.1111/jcmm.12450. View

Zhang Y, Chen B, Ding Y . Metastasis-associated factors facilitating the progression of colorectal cancer. Asian Pac J Cancer Prev. 2012; 13(6):2437-44. DOI: 10.7314/apjcp.2012.13.6.2437. View

Hu J, Wang S, Zhao Y, Guo Q, Zhang D, Chen J . Mechanism and biological significance of the overexpression of IFITM3 in gastric cancer. Oncol Rep. 2014; 32(6):2648-56. DOI: 10.3892/or.2014.3522. View

Zhao Y, Guo Q, Chen J, Hu J, Wang S, Sun Y . Role of long non-coding RNA HULC in cell proliferation, apoptosis and tumor metastasis of gastric cancer: a clinical and in vitro investigation. Oncol Rep. 2013; 31(1):358-64. DOI: 10.3892/or.2013.2850. View

Feng L, Wang X, Huang Q . Thymoquinone induces cytotoxicity and reprogramming of EMT in gastric cancer cells by targeting PI3K/Akt/mTOR pathway. J Biosci. 2017; 42(4):547-554. DOI: 10.1007/s12038-017-9708-3. View

10.

Zhang D, Wang H, He H, Niu H, Li Y . Interferon induced transmembrane protein 3 regulates the growth and invasion of human lung adenocarcinoma. Thorac Cancer. 2017; 8(4):337-343. PMC: 5494463. DOI: 10.1111/1759-7714.12451. View

11.

Lee J, Nam H, Kim L, Jeon Y, Min H, Ha S . TLR4 (toll-like receptor 4) activation suppresses autophagy through inhibition of FOXO3 and impairs phagocytic capacity of microglia. Autophagy. 2018; 15(5):753-770. PMC: 6526818. DOI: 10.1080/15548627.2018.1556946. View

12.

Torre L, Bray F, Siegel R, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. DOI: 10.3322/caac.21262. View

13.

Wu F, Dassopoulos T, Cope L, Maitra A, Brant S, Harris M . Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis. 2007; 13(7):807-21. DOI: 10.1002/ibd.20110. View

14.

Siegrist F, Ebeling M, Certa U . The small interferon-induced transmembrane genes and proteins. J Interferon Cytokine Res. 2010; 31(1):183-97. DOI: 10.1089/jir.2010.0112. View

15.

Chen Q, Jiao D, Wu Y, Chen J, Wang J, Tang X . MiR-206 inhibits HGF-induced epithelial-mesenchymal transition and angiogenesis in non-small cell lung cancer via c-Met /PI3k/Akt/mTOR pathway. Oncotarget. 2016; 7(14):18247-61. PMC: 4951285. DOI: 10.18632/oncotarget.7570. View

16.

Hou Y, Zhang Y, Qin L, Zhang C, Wang S, Chen D . Interferon-induced transmembrane protein-3 rs12252-CC is associated with low differentiation and progression of hepatocellular carcinoma. Medicine (Baltimore). 2019; 98(2):e13996. PMC: 6336587. DOI: 10.1097/MD.0000000000013996. View

17.

Massarweh N, El-Serag H . Epidemiology of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. Cancer Control. 2017; 24(3):1073274817729245. PMC: 5937247. DOI: 10.1177/1073274817729245. View

18.

Xu Q, Liu X, Liu Z, Zhou Z, Wang Y, Tu J . MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway. Mol Cancer. 2017; 16(1):103. PMC: 5469159. DOI: 10.1186/s12943-017-0675-y. View

19.

Jia Y, Xiao Z, Jiang W, Chen G, Wang Z . Overexpression of IFITM3 predicts poor prognosis in stage IIA esophageal squamous cell carcinoma after Ivor Lewis esophagectomy. Thorac Cancer. 2017; 8(6):592-599. PMC: 5668482. DOI: 10.1111/1759-7714.12488. View

20.

Zhu W, Xiao N, Liu X . Dietary flavonoid tangeretin induces reprogramming of epithelial to mesenchymal transition in prostate cancer cells by targeting the PI3K/Akt/mTOR signaling pathway. Oncol Lett. 2018; 15(1):433-440. PMC: 5766056. DOI: 10.3892/ol.2017.7307. View