Overexpression of calpain‑1 predicts poor outcome in patients with colorectal cancer and promotes tumor cell progression associated with downregulation of FLNA

Xu,Changzhao; Yu,Xiaoxiao; Zhu,Yuesheng; Cai,Zhenzhai; Yu,Lingmin; Lin,Ying; Yu,Hejie; Xue,Zhanxiong; Zhou,Lingling

doi:10.3892/or.2019.7121

Overexpression of calpain‑1 predicts poor outcome in patients with colorectal cancer and promotes tumor cell progression associated with downregulation of FLNA

Authors:
- Changzhao Xu
- Xiaoxiao Yu
- Yuesheng Zhu
- Zhenzhai Cai
- Lingmin Yu
- Ying Lin
- Hejie Yu
- Zhanxiong Xue
- Lingling Zhou
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Affiliations: Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Pathology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: April 16, 2019 https://doi.org/10.3892/or.2019.7121
Pages: 3424-3434

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Abstract

Several studies have demonstrated that calpain‑1 is involved in a variety of pathophysiological processes, including tumorigenesis. However, the clinical relevance and role of calpain‑1 in colorectal cancer (CRC) are unclear. Filamin A (FLNA) is an actin‑binding protein that participates in cancer progression and can be cleaved by calpain‑1. In the present study, the protein expression levels of calpain‑1 and FLNA were detected by immunohistochemistry in 467 matched cancerous and paracancerous tissues from patients with CRC. The staining results and the clinicopathological characteristics of the patients were comprehensively analyzed. A high expression level of calpain‑1 was strongly associated with age, metastasis, Dukes stage and survival time but not with sex, histologic grade, tumour location or tumor size. By contrast, a low expression level of FLNA was significantly associated with tumor size, histological grade, metastasis, Dukes stage and survival time, but not with age, sex, or tumor location. Kaplan‑Meier survival analysis demonstrated that patients with calpain‑1 overexpression had a shorter mean overall survival (OS) than patients with lower levels of calpain‑1 expression. Unlike high levels of calpain‑1, high levels of FLNA were associated with longer OS than lower levels of FLNA expression. Furthermore, calpain‑1 expression was inversely correlated with FLNA expression. The relationship between calpain‑1 and FLNA was further confirmed using CRC cell lines in vitro. When calpain‑1 expression decreased in CRC cells, FLNA expression increased. Furthermore, calpain‑1 knockdown in CRC cells resulted in decreased proliferation, colony formation, migration and invasion. The present findings suggest that calpain‑1 overexpression predicted a poor outcome in patients with CRC and promoted tumor progression, possibly via FLNA downregulation.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2	Cotton SW, Kornegay JN, Bogan DJ, Wadosky KM, Patterson C and Willis MS: Genetic myostatin decrease in the golden retriever muscular dystrophy model does not significantly affect the ubiquitin proteasome system despite enhancing the severity of disease. Am J Transl Res. 6:43–53. 2013.PubMed/NCBI
3	Arthur JS, Elce JS, Hegadorn C, Williams K and Greer PA: Disruption of the murine calpain small subunit gene, Capn4: Calpain is essential for embryonic development but not for cell growth and division. Mol Cell Biol. 20:4474–4481. 2000. View Article : Google Scholar : PubMed/NCBI
4	Suzuki K, Hata S, Kawabata Y and Sorimachi H: Structure, activation, and biology of calpain. Diabetes. 53 (Suppl 1):S12–S18. 2004. View Article : Google Scholar : PubMed/NCBI
5	Huang Y and Wang KK: The calpain family and human disease. Trends Mol Med. 7:355–362. 2001. View Article : Google Scholar : PubMed/NCBI
6	Gonzalez A, Abril E, Roca A, Aragón MJ, Figueroa MJ, Velarde P, Royo JL, Real LM and Ruiz A: CAPN10 alleles are associated with polycystic ovary syndrome. J Clin Endocrinol Metab. 87:3971–3976. 2002. View Article : Google Scholar : PubMed/NCBI
7	Ehrmann DA, Schwarz PE, Hara M, Tang X, Horikawa Y, Imperial J, Bell GI and Cox NJ: Relationship of calpain-10 genotype to phenotypic features of polycysticovary syndrome. J Clin Endocrinol Metab. 87:1669–1673. 2002. View Article : Google Scholar : PubMed/NCBI
8	Ohno S, Minoshima S, Kudoh J, Fukuyama R, Shimizu Y, Ohmi-Imajoh S, Shimizu N and Suzuki K: Four genes for the calpain family locate on four distinct human chromosomes. Cytogenet Cell Genet. 53:225–229. 1990. View Article : Google Scholar : PubMed/NCBI
9	Storr SJ, Thompson N, Pu X, Zhang Y and Martin SG: Calpain in breast cancer: Role in disease progression and treatment response. Pathobiology. 82:133–141. 2015. View Article : Google Scholar : PubMed/NCBI
10	Storr SJ, Carragher NO, Frame MC, Parr T and Martin SG: The calpain system and cancer. Nat Rev Cancer. 11:364–374. 2011. View Article : Google Scholar : PubMed/NCBI
11	Storr SJ, Woolston CM, Barros FF, Green AR, Shehata M, Chan SY, Ellis IO and Martin SG: Calpain-1 expression is associated with relapse-free survival in breast cancer patients treated with trastuzumab following adjuvant chemotherapy. Int J Cancer. 129:1773–1780. 2011. View Article : Google Scholar : PubMed/NCBI
12	Luo W, Ren Z, Gao S, Jin H, Zhang G, Zhou L and Zheng S: Clinical correlation of calpain-1 and glypican-3 expression with gallbladder carcinoma. Oncol Lett. 11:1345–1352. 2016. View Article : Google Scholar : PubMed/NCBI
13	Salehin D, Fromberg I, Haugk C, Dohmen B, Georg T, Bohle RM, Bauerschlag D, Maass N and Friedrich M: Immunhistochemical analysis for expression of calpain 1, calpain 2 and calpastatin in endometrial cancer. Anticancer Res. 30:2837–2843. 2010.PubMed/NCBI
14	Kovacs L and Su Y: The critical role of calpain in cell proliferation. Biomol Res Ther. 3:1122014.
15	Tian ZQ, Shi JW, Wang XR, Li Z and Wang GY: New cancer suppressor gene for colorectal adenocarcinoma: Filamin A. World J Gastroenterol. 21:2199–2205. 2015. View Article : Google Scholar : PubMed/NCBI
16	Guroff G: A neutral, calcium-activated proteinase from the soluble fraction of rat brain. J Biol Chem. 239:149–155. 1964.PubMed/NCBI
17	Azam M, Andrabi SS, Sahr KE, Kamath L, Kuliopulos A and Chishti AH: Disruption of the mouse mu-calpain gene reveals an essential role in platelet function. Mol Cell Biol. 21:2213–2220. 2001. View Article : Google Scholar : PubMed/NCBI
18	Sorimachi H, Hata S and Ono Y: Impact of genetic insights into calpain biology. J Biochem. 150:23–37. 2011. View Article : Google Scholar : PubMed/NCBI
19	Van Ba H and Inho H: Significant role of µ-calpain (CANP1) in proliferation/survival of bovine skeletal muscle satellite cells. In vitro Cell Dev Biol Anim. 49:785–797. 2013. View Article : Google Scholar : PubMed/NCBI
20	Santella L, Kyozuka K, De Riso L and Carafoli E: Calcium, protease action, and the regulation of the cell cycle. Cell Calcium. 23:123–130. 1998. View Article : Google Scholar : PubMed/NCBI
21	Wang KK: Calpain and caspase: Can you tell the difference? Trends Neurosci. 23:20–26. 2000. View Article : Google Scholar : PubMed/NCBI
22	Braun C, Engel M, Seifert M, Theisinger B, Seitz G, Zang KD and Welter C: Expression of calpain I messenger RNA in human renal cell carcinoma: Correlation with lymph node metastasis and histological type. Int J Cancer. 84:6–9. 1999. View Article : Google Scholar : PubMed/NCBI
23	Delmas C, Aragou N, Poussard S, Cottin P, Darbon JM and Manenti S: MAP kinase-dependent degradation of p27Kip1 by calpains in choroidal melanoma cells. Requirement of p27Kip1 nuclear export. J Biol Chem. 278:12443–12451. 2003. View Article : Google Scholar : PubMed/NCBI
24	Ma D, Fang J, Liu Y, Song JJ, Wang YQ, Xia J, Cheng B and Wang Z: High level of calpain1 promotes cancer cell invasion and migration in oral squamous cell carcinoma. Oncol Lett. 13:4017–4026. 2017. View Article : Google Scholar : PubMed/NCBI
25	Salimi R, Bandaru S, Devarakonda S, Gökalp S, Ala C, Alvandian A, Yener N and Akyürek LM: Blocking the cleavage of filamin A by calpain inhibitor decreases tumor cell growth. Anticancer Res. 38:2079–2085. 2018.PubMed/NCBI
26	O'Connell MP, Fiori JL, Baugher KM, Indig FE, French AD, Camilli TC, Frank BP, Earley R, Hoek KS, Hasskamp JH, et al: Wnt5A activates the calpain-mediated cleavage of filamin A. J Invest Dermatol. 129:1782–1789. 2009. View Article : Google Scholar : PubMed/NCBI