HCRP1 downregulation confers poor prognosis and induces chemoresistance through regulation of EGFR-AKT pathway in human gastric cancer
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The current study aims to investigate the biological roles and clinical significance of HCRP1 in human gastric cancer. The expression pattern of HCRP1 in gastric cancer tissue and adjacent non-cancerous tissue was detected by immunohistochemistry. HCRP1 downregulation was found in 57 of 137 human gastric cancer samples and correlated with advanced TNM stage, positive nodal status, and relapse. Log-rank test showed that HCRP1 downregulation also correlated with poor overall survival and reduced relapse-free survival. In addition, we found that HCRP1 overexpression inhibited proliferation, colony formation, and invasion in HGC-27 cells. On the other hand, HCRP1 depletion by small interfering RNA promoted proliferation, colony formation, and invasion in SGC-7901 cells. We also treated gastric cancer cells with cisplatin. MTT and Annexin V/PI analysis were carried out to examine change of chemoresistance. We found that HCRP1 overexpression sensitized HGC-27 cells to cisplatin while its depletion reduced sensitivity in SGC-7901 cells. Moreover, we found that HCRP1 overexpression negatively regulated cyclin D1, MMP-2, p-EGFR, p-ERK, and p-AKT. HCRP1 depletion showed the opposite effects. In conclusion, our results suggest that HCRP1 downregulation might serve as an indicator for poor prognosis in gastric cancer patients. HCRP1 reduces drug resistance through regulation of EGFR-AKT signaling.
KeywordsHCRP1 Gastric cancer Cell cycle Resistance
We thank Prof. Feng Li for technical guidance and assistance.
Hao Xu and Zhi-Feng Miao designed the study and wrote the manuscript; Hao Xu and Zhen-Ning Wang collected the tissue sections; Hui-Mian Xu contributed to the study design and paper accomplishment; Ting-Ting Zhao and Ying-Ying Xu performed the MTT and flow cytometry assays; Hao Xu and Yong-Xi Song performed the cell culture, transfection, and western blot assays; Zhi-Feng Miao, Jin-Yu Huang, and Jun-Yan Zhang performed the immunohistochemistry, colony formation, and matrigel invasion assay; Xing-Yu Liu and Jian-Hua Wu analyzed the data. All authors participated in discussing the content of the paper and read and approved the final manuscript.
This work was supported by the National Science Foundation of China (grant numbers: 81272718 and 81302125).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
The protocols of this study have been approved by the Ethics committee of China Medical University (reference number 2016-AF-03).
- 5.Polom K, Marano L, Roviello G, Petrioli R, Piagnerelli R, de Franco L, Marrelli D, Roviello F (2016) Evolution and emerging future of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion in gastric cancer: from treating the incurable to preventing recurrence. Int J Hyperth 32(2):173–179. https://doi.org/10.3109/02656736.2015.1111432 CrossRefGoogle Scholar
- 7.Nadauld LD, Garcia S, Natsoulis G, Bell JM, Miotke L, Hopmans ES, Xu H, Pai RK, Palm C, Regan JF, Chen H, Flaherty P, Ootani A, Zhang NR, Ford JM, Kuo CJ, Ji HP (2014) Metastatic tumor evolution and organoid modeling implicate TGFBR2 as a cancer driver in diffuse gastric cancer. Genome Biol 15(8):428. https://doi.org/10.1186/s13059-014-0428-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Bache KG, Slagsvold T, Cabezas A, Rosendal KR, Raiborg C, Stenmark H (2004) The growth-regulatory protein HCRP1/hVps37A is a subunit of mammalian ESCRT-I and mediates receptor down-regulation. Mol Biol Cell 15(9):4337–4346. https://doi.org/10.1091/mbc.E04-03-0250 CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Perisanidis C, Savarese-Brenner B, Wurger T, Wrba F, Huynh A, Schopper C, Kornek G, Selzer E, Ewers R, Psyrri A, Krainer M, Filipits M (2013) HCRP1 expression status is a significant prognostic marker in oral and oropharyngeal cancer. Oral Dis 19(2):206–211. https://doi.org/10.1111/j.1601-0825.2012.01972.x CrossRefPubMedGoogle Scholar
- 13.Wittinger M, Vanhara P, El-Gazzar A, Savarese-Brenner B, Pils D, Anees M, Grunt TW, Sibilia M, Holcmann M, Horvat R, Schemper M, Zeillinger R, Schöfer C, Dolznig H, Horak P, Krainer M (2011) hVps37A status affects prognosis and cetuximab sensitivity in ovarian cancer. Clin Cancer Res 17(4):7816–7827. https://doi.org/10.1158/1078-0432.CCR-11-0408 CrossRefPubMedGoogle Scholar
- 14.Xu J, Zhang X, Wang H, Ge S, Gao T, Song L, Wang X, Li H, Qin Y, Zhang Z (2017) HCRP1 downregulation promotes hepatocellular carcinoma cell migration and invasion through the induction of EGFR activation and epithelial-mesenchymal transition. Biomed Pharmacother 88:421–429. https://doi.org/10.1016/j.biopha.2017.01.013 CrossRefPubMedGoogle Scholar
- 15.Du Y, Wang P, Sun H, Yang J, Lang X, Wang Z, Zang S, Chen L, Ma J, Sun D (2016) HCRP1 is downregulated in non-small cell lung cancer and regulates proliferation, invasion, and drug resistance. Tumour Biol. https://doi.org/10.1007/s13277-016-5416-0
- 18.Kim JY, Park SY, Lyoo HR, Koo ES, Kim MS, Jeong YS (2015) Extended stability of cyclin D1 contributes to limited cell cycle arrest at G1-phase in BHK-21 cells with Japanese encephalitis virus persistent infection. J Microbiol 53(1):77–83. https://doi.org/10.1007/s12275-015-4661-z CrossRefPubMedGoogle Scholar
- 19.Cheng G, Zhang L, Lv W, Dong C, Wang Y, Zhang J (2015) Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. Med Oncol 32(1):439. https://doi.org/10.1007/s12032-014-0439-0 CrossRefPubMedGoogle Scholar
- 22.Kumar AP, Bhaskaran S, Ganapathy M, Crosby K, Davis MD, Kochunov P, Schoolfield J, Yeh IT, Troyer DA, Ghosh R (2007) Akt/cAMP-responsive element binding protein/cyclin D1 network: a novel target for prostate cancer inhibition in transgenic adenocarcinoma of mouse prostate model mediated by Nexrutine, a Phellodendron amurense bark extract. Clin Cancer Res 13(9):2784–2794. https://doi.org/10.1158/1078-0432.CCR-06-2974 CrossRefPubMedPubMedCentralGoogle Scholar