CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway

Li,Linjin; Hu,Yiren; Chen,Dake; Zhu,Jianlong; Bao,Wenshuo; Xu,Xiaomin; Chen,Heyi; Chen,Wu; Feng,Rui

doi:10.3892/mmr.2021.12533

CMTM5 inhibits the development of prostate cancer via the EGFR/PI3K/AKT signaling pathway

Authors:
- Linjin Li
- Yiren Hu
- Dake Chen
- Jianlong Zhu
- Wenshuo Bao
- Xiaomin Xu
- Heyi Chen
- Wu Chen
- Rui Feng
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Affiliations: Department of Urology, The Third Clinical Institute Affiliated to Wenzhou Medical University, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, P.R. China, Department of Urology, Zhenjiang Hospital of Chinese Traditional and Western Medicine, Zhenjiang, Jiangsu 212002, P.R. China
Published online on: November 15, 2021 https://doi.org/10.3892/mmr.2021.12533
Article Number: 17
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Prostate cancer (PCa) endangers the life and health of older men. Most PCa cases develop into castration‑resistant PCa (CRPC) within 2 years. At present, the molecular mechanisms of the occurrence and development of PCa and its transformation to CRPC remain unknown. The present study aimed to investigate the role of CKLF‑like Marvel transmembrane domain containing family member 5 (CMTM5) in PCa and its molecular mechanism in vitro. PCa tissues and paired adjacent normal prostate tissues from 70 patients were collected to examine the expression levels of CMTM5 and EGFR via immunohistochemistry, reverse transcription‑quantitative PCR and western blotting. Then, CMTM5‑overexpressing DU145 cells were constructed, and CMTM5 expression in these transfected cells and vector control cells was examined via western blotting. Cell Counting Kit‑8 and plate clone formation assays were used to evaluate the proliferation and colony number of CMTM5‑overexpressing cells and vector control cells. Then, cell migration and invasion were assessed using wound healing assay, Transwell assay and immunofluorescence analysis with DAPI staining. The effect of CMTM5 on apoptosis and its underlying molecular mechanism were examined using western blotting and flow cytometry. The results demonstrated that CMTM5 expression in PCa tissues and cell lines was significantly downregulated, while EFGR expression was significantly upregulated. The proportion of high CMTM5 expression in PCa tissues was significantly lower compared with that in normal prostate tissues. By contrast, the proportion of high EGFR expression in PCa tissues was significantly increased compared with that in normal prostate tissues. Moreover, CMTM5 overexpression significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis compared with vector control cells in vitro. Furthermore, the regulation of PCa by CMTM5 was associated with the downregulation of PI3K/AKT and its downstream Bcl‑2 expression, as well as the upregulation of Bax expression. In conclusion, CMTM5 may be an effective tumor suppressor gene for PCa, especially for castration‑resistant PCa, by downregulating EGFR and PI3K/AKT signaling pathway components.

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1	Siegel RL, Miller K and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Zhuo L, Cheng Y, Pan Y, Zong J, Sun W, Xu L, Soriano-Gabarró M, Song Y, Lu J and Zhan S: Prostate cancer with bone metastasis in Beijing: An observational study of prevalence, hospital visits and treatment costs using data from an administrative claims database. BMJ Open. 9:e0282142019. View Article : Google Scholar : PubMed/NCBI
3	Jia Y, Zhu LY, Xian YX, Sun XQ, Gao JG, Zhang XH, Hou SC, Zhang CC and Liu ZX: Detection rate of prostate cancer following biopsy among the northern Han Chinese population: A single-center retrospective study of 1022 cases. World J Surg Oncol. 15:1652017. View Article : Google Scholar : PubMed/NCBI
4	Wu G, Huang S, Nastiuk KL, Li J, Gu J, Wu M, Zhang Q, Lin H and Wu D: Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer. Prostate. 75:777–782. 2015. View Article : Google Scholar : PubMed/NCBI
5	Mimeault M and Batra SK: Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis. 27:1–22. 2006. View Article : Google Scholar : PubMed/NCBI
6	Peraldo-Neia C, Migliardi G, Mello-Grand M, Montemurro F, Segir R, Pignochino Y, Cavalloni G, Torchio B, Mosso L, Chiorino G and Aglietta M: Epidermal Growth Factor Receptor (EGFR) mutation analysis, gene expression profiling and EGFR protein expression in primary prostate cancer. BMC Cancer. 11:312011. View Article : Google Scholar : PubMed/NCBI
7	Mitsunari K, Miyata Y, Asai A, Matsuo T, Shida Y, Hakariya T and Sakai H: Human antigen R is positively associated with malignant aggressiveness via upregulation of cell proliferation, migration, and vascular endothelial growth factors and cyclooxygenase-2 in prostate cancer. Transl Res. 175:116–128. 2016. View Article : Google Scholar : PubMed/NCBI
8	Pan M, Schinke H, Luxenburger E, Kranz G, Shakhtour J, Libl D, Huang Y, Gaber A, Pavšič M, Lenarčič B, et al: EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGF-mediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers. PLoS Biol. 16:e20066242018. View Article : Google Scholar : PubMed/NCBI
9	Yuan W, Liu B, Wang X, Li T, Xue H, Mo X, Yang S, Ding S and Han W: CMTM3 decreases EGFR expression and EGF-mediated tumorigenicity by promoting Rab5 activity in gastric cancer. Cancer Lett. 386:77–86. 2017. View Article : Google Scholar : PubMed/NCBI
10	Tsai PC, Fu YS, Chang LS and Lin SR: Taiwan cobra cardiotoxin III suppresses EGF/EGFR-mediated epithelial-to-mesenchymal transition and invasion of human breast cancer MDA-MB-231 cells. Toxicon. 111:108–120. 2016. View Article : Google Scholar : PubMed/NCBI
11	Clapéron A, Mergey M, Nguyen Ho-Bouldoires TH, Vignjevic D, Wendum D, Chrétien Y, Merabtene F, Frazao A, Paradis V, Housset C, et al: EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition. J Hepatol. 61:325–332. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Hu J, Wang Y, Ye W, Zhang X, Ju H, Xu D, Liu L, Ye D, Zhang L, et al: EGFR activation induced Snail-dependent EMT and myc-dependent PD-L1 in human salivary adenoid cystic carcinoma cells. Cell Cycle. 17:1457–1470. 2018. View Article : Google Scholar : PubMed/NCBI
13	Jathal MK, Steele TM, Siddiqui S, Mooso BA, D'Abronzo LS, Drake CM, Whang YE and Ghosh PM: Dacomitinib, but not lapatinib, suppressed progression in castration-resistant prostate cancer models by preventing HER2 increase. Br J Cancer. 121:237–248. 2019. View Article : Google Scholar : PubMed/NCBI
14	Bender R and Gabhann FM: Dysregulation of the vascular endothelial growth factor and semaphorin ligand-receptor families in prostate cancer metastasis. BMC Syst Biol. 9:552015. View Article : Google Scholar : PubMed/NCBI
15	Han W, Ding P, Xu M, Wang L, Rui M, Shi S, Liu Y, Zheng Y, Chen Y, Yang T and Ma D: Identification of eight genes encoding chemokine-like factor superfamily members 1-8 (CKLFSF1-8) by in silico cloning and experimental validation. Genomics. 81:609–617. 2003. View Article : Google Scholar : PubMed/NCBI
16	Li H, Guo X, Shao L, Plate M, Mo X, Wang Y and Han W: CMTM5-v1, a four-transmembrane protein, presents a secreted form released via a vesicle-mediated secretory pathway. J Biochem Mol Biol. 43:182–187. 2010.PubMed/NCBI
17	Liu B, Su Y, Li T, Yuan W, Mo X, Li H, He Q, Ma D and Han W: CMTM7 knockdown increases tumorigenicity of human non-small cell lung cancer cells and EGFR-AKT signaling by reducing Rab5 activation. Oncotarget. 6:41092–41107. 2015. View Article : Google Scholar : PubMed/NCBI
18	Li H, Li J, Su Y, Fan Y, Guo X, Li L, Su X, Rong R, Ying J, Mo X, et al: A novel 3p22.3 gene CMTM7 represses oncogenic EGFR signaling and inhibits cancer cell growth. Oncogene. 33:3109–3118. 2014. View Article : Google Scholar : PubMed/NCBI
19	Both J, Krijgsman O, Bras J, Schaap GR, Baas F, Ylstra B and Hulsebos TJ: Focal chromosomal copy number aberrations identify CMTM8 and GPR177 as new candidate driver genes in osteosarcoma. PLoS One. 9:e1158352014. View Article : Google Scholar : PubMed/NCBI
20	Chang SS and Amin MB: Utilizing the tumor-node-metastasis staging for prostate cancer: The sixth edition, 2002. CA Cancer J Clin. 58:54–59. 2008. View Article : Google Scholar : PubMed/NCBI
21	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 : PubMed/NCBI
22	Shao L, Cui Y, Li H, Liu Y, Zhao H, Wang Y, Zhang Y, Ng KM, Han W, Ma D and Tao Q: CMTM5 exhibits tumor suppressor activities and is frequently silenced by methylation in carcinoma cell lines. Clin Cancer Res. 13:5756–5762. 2007. View Article : Google Scholar : PubMed/NCBI
23	Guo X, Li T, Wang Y, Shao L, Zhang Y, Ma D and Han W: CMTM5 induces apoptosis of pancreatic cancer cells and has synergistic effects with TNF-alpha. Biochem Biophys Res Commun. 387:139–142. 2009. View Article : Google Scholar : PubMed/NCBI
24	Shao L, Guo X, Plate M, Li T, Wang Y, Ma D and Han W: CMTM5-v1 induces apoptosis in cervical carcinoma cells. Biochem Biophys Res Commun. 379:866–871. 2009. View Article : Google Scholar : PubMed/NCBI
25	Huang ZM, Li PL, Yang P, Hou XD, Yang YL, Xu X and Xu F: Overexpression of CMTM7 inhibits cell growth and migration in liver cancer. Kaohsiung J Med Sci. 35:332–340. 2019.PubMed/NCBI
26	Montanari M, Rossetti S, Cavaliere C, D'Aniello C, Malzone MG, Vanacore D, Di Franco R, La Mantia E, Iovane G, Piscitelli R, et al: Epithelial-mesenchymal transition in prostate cancer: An overview. Oncotarget. 8:35376–3589. 2017. View Article : Google Scholar : PubMed/NCBI
27	Wang L, Song G, Tan W, Qi M, Zhang L, Chan J, Yu J, Han J and Han B: MiR-573 inhibits prostate cancer metastasis by regulating epithelial-mesenchymal transition. Oncotarget. 6:35978–35990. 2015. View Article : Google Scholar : PubMed/NCBI
28	Lai Y, Kong Z, Zeng T, Xu S, Duan X, Li S, Cai C, Zhao Z and Wu W: PARP1-siRNA suppresses human prostate cancer cell growth and progression. Oncol Rep. 39:1901–1909. 2018.PubMed/NCBI
29	Nieto MA, Huang RY, Jackson RA and Thiery JP: EMT: 2016. Cell. 166:21–45. 2016. View Article : Google Scholar : PubMed/NCBI
30	Hu F, Yuan W, Wang X, Sheng Z, Yuan Y, Qin C, He C and Xu T: CMTM3 is reduced in prostate cancer and inhibits migration, invasion and growth of LNCaP cells. Clin Transl Oncol. 17:632–639. 2015. View Article : Google Scholar : PubMed/NCBI
31	Guan L, Ji D, Liang N, Li S and Sun B: Up-regulation of miR-10b-3p promotes the progression of hepatocellular carcinoma cells via targeting CMTM5. J Cell Mol Med. 22:3434–3441. 2018. View Article : Google Scholar : PubMed/NCBI
32	Cai B, Xiao Y, Li Y and Zheng S: CMTM5 inhibits renal cancer cell growth through inducing cell-cycle arrest and apoptosis. Oncol Lett. 14:1536–1542. 2017. View Article : Google Scholar : PubMed/NCBI
33	Chen H, Zhou L, Wu X, Li R, Wen J, Sha J and Wen X: The PI3K/AKT pathway in the pathogenesis of prostate cancer. Front Biosci (Landmark Ed). 21:1084–1091. 2016. View Article : Google Scholar : PubMed/NCBI
34	Xiao Y, Yuan Y, Zhang Y, Li J, Liu Z, Zhang X, Sheng Z, Xu T and Wang X: CMTM5 is reduced in prostate cancer and inhibits cancer cell growth in vitro and in vivo. Clin Transl Oncol. 17:431–437. 2015. View Article : Google Scholar : PubMed/NCBI
35	Yu JS and CUI W: Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development. 143:3050–3060. 2016. View Article : Google Scholar : PubMed/NCBI