Clinical significance and functional role of transmembrane protein 47 (TMEM47) in chemoresistance of hepatocellular carcinoma

Ng,Kevin  Tak‑Pan; Yeung,Oscar  Wai‑Ho; Liu,Jiang; Li,Chang  Xian; Liu,Hui; Liu,Xiao   Bing; Qi,Xiang; Ma,Yuen  Yuen; Lam,Yin  Fan; Lau,Matthew  Yh; Qiu,Wen  Qi; Shiu,Hoi   Chung; Lai,Man   Kit; Lo,Chung  Mau; Man,Kwan

doi:10.3892/ijo.2020.5104

Clinical significance and functional role of transmembrane protein 47 (TMEM47) in chemoresistance of hepatocellular carcinoma

Authors:
- Kevin Tak‑Pan Ng
- Oscar Wai‑Ho Yeung
- Jiang Liu
- Chang Xian Li
- Hui Liu
- Xiao Bing Liu
- Xiang Qi
- Yuen Yuen Ma
- Yin Fan Lam
- Matthew Yh Lau
- Wen Qi Qiu
- Hoi Chung Shiu
- Man Kit Lai
- Chung Mau Lo
- Kwan Man
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Affiliations: Department of Surgery, The University of Hong Kong Shenzhen Hospital and LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, P.R. China
Published online on: July 28, 2020 https://doi.org/10.3892/ijo.2020.5104
Pages: 956-966
Copyright: © Ng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Chemoresistance is the main cause of chemotherapy failure in patients with hepatocellular carcinoma (HCC). The gene encoding transmembrane protein 47 (TMEM47) was previously identified to be significantly upregulated in HCC cell lines with acquired chemoresistance. The aim of the present study was to characterize the clinical significance and function of TMEM47 in HCC chemoresistance. The results demonstrated that the TMEM47 expression levels in the tumors of patients not responding to cisplatin‑based transarterial chemoembolization (TACE) treatment was significantly higher compared with those in patients who responded to TACE treatment. Moreover, analyses from clinical samples and HCC cell lines indicated that TMEM47 expression may be upregulated in HCC in response to cisplatin treatment. Furthermore, the TMEM47 mRNA expression levels were positively correlated with the degree of cisplatin resistance of HCC cells. Overexpression of TMEM47 in HCC cells significantly promoted cisplatin resistance. The present study also demonstrated that targeted inhibition of TMEM47 could significantly reduce cisplatin resistance of cisplatin‑resistant HCC cells via enhancing caspase‑mediated apoptosis. In addition, targeted inhibition of TMEM47 enhanced the sensitivity of cisplatin‑resistant cells to cisplatin via suppressing cisplatin‑induced activation of the genes involved in drug efflux and metabolism. The present study also validated that TMEM47 expression was significantly correlated with multidrug resistance‑associated protein 1 in patients with HCC who received TACE treatment. In conclusion, the findings of the present study demonstrated that TMEM47 may be a useful biomarker for predicting the response to chemotherapy and a potential therapeutic target for overcoming HCC chemoresistance.

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1	Villanueva A: Hepatocellular carcinoma. N Engl J Med. 380:1450–1462. 2019. View Article : Google Scholar : PubMed/NCBI
2	Zhu AX: Systemic therapy of advanced hepatocellular carcinoma: How hopeful should we be? Oncologist. 11:790–800. 2006. View Article : Google Scholar : PubMed/NCBI
3	Worns MA, Weinmann A, Schuchmann M and Galle PR: Systemic therapies in hepatocellular carcinoma. Dig Dis. 27:175–188. 2009. View Article : Google Scholar : PubMed/NCBI
4	Lohitesh K, Chowdhury R and Mukherjee S: Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: An insight. Cancer Cell Int. 18:442018. View Article : Google Scholar : PubMed/NCBI
5	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
6	Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. 391:1163–1173. 2018. View Article : Google Scholar : PubMed/NCBI
7	da Motta Girardi D, Correa TS, Crosara Teixeira M and Dos Santos Fernandes G: Hepatocellular carcinoma: Review of targeted and immune therapies. J Gastrointest Cancer. 49:227–236. 2018. View Article : Google Scholar : PubMed/NCBI
8	Faivre S, Rimassa L and Finn RS: Molecular therapies for HCC: Looking outside the box. J Hepatol. 72:342–352. 2020. View Article : Google Scholar : PubMed/NCBI
9	Dasari S and Tchounwou PB: Cisplatin in cancer therapy: Molecular mechanisms of action. Eur J Pharmacol. 740:364–378. 2014. View Article : Google Scholar : PubMed/NCBI
10	Ikeda K: Recent advances in medical management of hepatocellular carcinoma. Hepatol Res. 49:14–32. 2019. View Article : Google Scholar
11	Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M and Kroemer G: Molecular mechanisms of cisplatin resistance. Oncogene. 31:1869–1883. 2012. View Article : Google Scholar
12	Koberle B, Tomicic MT, Usanova S and Kaina B: Cisplatin resistance: Preclinical findings and clinical implications. Biochim Biophys Acta. 1806:172–182. 2010.PubMed/NCBI
13	Makovec T: Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiol Oncol. 53:148–158. 2019. View Article : Google Scholar : PubMed/NCBI
14	Pratama MY, Pascut D, Massi MN and Tiribelli C: The role of microRNA in the resistance to treatment of hepatocellular carcinoma. Ann Transl Med. 7:5772019. View Article : Google Scholar : PubMed/NCBI
15	Llovet JM and Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 37:429–442. 2003. View Article : Google Scholar : PubMed/NCBI
16	Raoul JL, Forner A, Bolondi L, Cheung TT, Kloeckner R and de Baere T: Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. Cancer Treat Rev. 72:28–36. 2019. View Article : Google Scholar
17	Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solá R, et al: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet. 359:1734–1739. 2002. View Article : Google Scholar : PubMed/NCBI
18	Ng KT, Lo CM, Guo DY, Qi X, Li CX, Geng W, Liu XB, Ling CC, Ma YY, Yeung WH, et al: Identification of transmembrane protein 98 as a novel chemoresistance-conferring gene in hepatocellular carcinoma. Mol Cancer Ther. 13:1285–1297. 2014. View Article : Google Scholar : PubMed/NCBI
19	Dong Y and Simske JS: Vertebrate Claudin/PMP22/EMP22/MP20 family protein TMEM47 regulates epithelial cell junction maturation and morphogenesis. Dev Dyn. 245:653–666. 2016. View Article : Google Scholar : PubMed/NCBI
20	Burnett RM, Craven KE, Krishnamurthy P, Goswami CP, Badve S, Crooks P, Mathews WP, Bhat-Nakshatri P and Nakshatri H: Organ-specific adaptive signaling pathway activation in meta-static breast cancer cells. Oncotarget. 6:12682–12696. 2015. View Article : Google Scholar : PubMed/NCBI
21	Cheung IY, Feng Y, Danis K, Shukla N, Meyers P, Ladanyi M and Cheung NK: Novel markers of subclinical disease for Ewing family tumors from gene expression profiling. Clin Cancer Res. 13:6978–6983. 2007. View Article : Google Scholar : PubMed/NCBI
22	Mithani SK, Smith IM and Califano JA: Use of integrative epigenetic and cytogenetic analyses to identify novel tumor-suppressor genes in malignant melanoma. Melanoma Res. 21:298–307. 2011. View Article : Google Scholar : PubMed/NCBI
23	Poon RT, Ngan H, Lo CM, Liu CL, Fan ST and Wong J: Transarterial chemoembolization for inoperable hepatocellular carcinoma and postresection intrahepatic recurrence. J Surg Oncol. 73:109–114. 2000. View Article : Google Scholar : PubMed/NCBI
24	Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Chen J, Gao DM and Bao WH: Establishment of cell clones with different meta-static potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol. 7:630–636. 2001. View Article : Google Scholar
25	Ng KT, Xu A, Cheng Q, Guo DY, Lim ZX, Sun CK, Fung JH, Poon RT, Fan ST, Lo CM, et al: Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocel-lular carcinoma. Mol Cancer. 13:1962014. View Article : Google Scholar
26	Ng KT, Qi X, Kong KL, Cheung BY, Lo CM, Poon RT, Fan ST and Man K: Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with poor prognosis of hepatocellular carcinoma. Eur J Cancer. 47:2299–305. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ng KT, Lee TK, Cheng Q, Wo JY, Sun CK, Guo DY, Lim ZX, Lo CM, Poon RT, Fan ST, et al: Suppression of tumorigenesis and metastasis of hepatocellular carcinoma by shRNA interference targeting on homeoprotein Six1. Int J Cancer. 127:859–872. 2010.
28	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
29	Liu XY, Liu SP, Jiang J, Zhang X and Zhang T: Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein. Eur Rev Med Pharmacol Sci. 20:1098–1108. 2016.PubMed/NCBI
30	Yau T, Chan P, Epstein R and Poon RT: Management of advanced hepatocellular carcinoma in the era of targeted therapy. Liver Int. 29:10–17. 2009. View Article : Google Scholar : PubMed/NCBI
31	Wysocki PJ: Targeted therapy of hepatocellular cancer. Expert Opin Investig Drugs. 19:265–274. 2010. View Article : Google Scholar : PubMed/NCBI
32	Duan B, Huang C, Bai J, Zhang YL, Wang X, Yang J and Li J: Multidrug resistance in hepatocellular carcinoma. Hepatocellular Carcinoma. Tirnitz-Parker JEE: Codon Publications; Brisbane, AU: 2019, View Article : Google Scholar
33	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245. 2012. View Article : Google Scholar : PubMed/NCBI
34	Takayasu K, Arii S, Ikai I, Omata M, Okita K, Ichida T, Matsuyama Y, Nakanuma Y, Kojiro M, Makuuchi M, et al: Prospective cohort study of transarterial chemoembolization for unresectable hepatocellular carcinoma in 8510 patients. Gastroenterology. 131:461–469. 2006. View Article : Google Scholar : PubMed/NCBI
35	Volkmann M, Schiff JH, Hajjar Y, Otto G, Stilgenbauer F, Fiehn W, Galle PR and Hofmann WJ: Loss of CD95 expression is linked to most but not all p53 mutants in European hepatocellular carcinoma. J Mol Med (Berl). 79:594–600. 2001. View Article : Google Scholar
36	Schattenberg JM, Galle PR and Schuchmann M: Apoptosis in liver disease. Liver Int. 26:904–911. 2006. View Article : Google Scholar : PubMed/NCBI
37	Chun E and Lee KY: Bcl-2 and Bcl-xL are important for the induction of paclitaxel resistance in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 315:771–779. 2004. View Article : Google Scholar : PubMed/NCBI
38	Chan KT and Lung ML: Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol. 53:519–526. 2004. View Article : Google Scholar : PubMed/NCBI
39	Mondal J and Khuda-Bukhsh AR: Cisplatin and farnesol co-encapsulated PLGA nano-particles demonstrate enhanced anti-cancer potential against hepatocellular carcinoma cells in vitro. Mol Biol Rep. 47:3615–3628. 2020. View Article : Google Scholar : PubMed/NCBI
40	Cassim S, Raymond VA, Dehbidi-Assadzadeh L, Lapierre P and Bilodeau M: Metabolic reprogramming enables hepatocarcinoma cells to efficiently adapt and survive to a nutrient-restricted microenvironment. Cell Cycle. 17:903–916. 2018. View Article : Google Scholar : PubMed/NCBI