Collagen type VI‑α1 and 2 repress the proliferation, migration and invasion of bladder cancer cells

Piao,Xuan-Mei; Hwang,Byungdoo; Jeong,Pildu; Byun,Young Joon; Kang,Ho Won; Seo,Sung Phil; Kim,Won Tae; Lee,Jong-Young; Ha,Yun-Sok; Lee,Young-Suk; Kim,Isaac Y.; Choi,Yung Hyun; Cha,Eun-Jong; Moon,Sung-Kwon; Yun,Seok Joong; Kim,Wun-Jae

doi:10.3892/ijo.2021.5217

Collagen type VI‑α1 and 2 repress the proliferation, migration and invasion of bladder cancer cells

Authors:
- Xuan-Mei Piao
- Byungdoo Hwang
- Pildu Jeong
- Young Joon Byun
- Ho Won Kang
- Sung Phil Seo
- Won Tae Kim
- Jong-Young Lee
- Yun-Sok Ha
- Young-Suk Lee
- Isaac Y. Kim
- Yung Hyun Choi
- Eun-Jong Cha
- Sung-Kwon Moon
- Seok Joong Yun
- Wun-Jae Kim
View Affiliations

Affiliations: Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungcheongbuk 28644, Republic of Korea, Department of Food Science and Technology, Chung‑Ang University, Anseong, Gyeonggi 456‑756, Republic of Korea, Oneomics Institute, Seoul 04158, Republic of Korea, Department of Urology, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea, Department of Urology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Gyeongsangnam 51353, Republic of Korea, Section of Urologic Oncology and Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, NJ 08903‑2681, USA, Department of Biochemistry, College of Oriental Medicine, Dong‑Eui University, Busan 614‑052, Republic of Korea, Department of Biomedical Engineering, Chungbuk National University College of Medicine, Cheongju, Chungcheongbuk 28644, Republic of Korea
Published online on: May 7, 2021 https://doi.org/10.3892/ijo.2021.5217
Article Number: 37

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The bladder cancer (BCa) microenvironment comprises heterogeneous tumor cell populations, the surrounding stroma and the extracellular matrix (ECM). Collagen, the scaffold of the tumor microenvironment, regulates ECM remodeling to promote tumor infiltration, angiogenesis, invasion and migration. The present study examined how collagen type VI‑α (COL6A) 1 and 2 function during BCa pathogenesis and progression, with the aim of facilitating the development of precision therapeutics, risk stratification and molecular diagnosis. COL6A1 and COL6A2 mRNA expression in non‑muscle invasive BCa (NMIBC) and MIBC tissue samples was measured using reverse transcription‑quantitative PCR. In addition, the tumor‑suppressive effects of COL6A1 and COL6A2 in human BCa EJ cells (MGH‑U1) were assessed. Compared with normal controls, COL6A1 and COL6A2 mRNA expression was downregulated in both NMIBC and MIBC tissue samples (P<0.05, respectively). COL6A1 and COL6A2 effectively inhibited the proliferation of human BCa EJ cells (MGH‑U1) and induced cell cycle arrest at the G₁ phase. Additionally, COL6A1 and COL6A2 served roles in MAPK and AKT signaling by increasing p38 MAPK phosphorylation and decreasing AKT phosphorylation. Finally, COL6A1 and COL6A2 inhibited wound healing and invasion by suppressing the activity of matrix metalloproteinase (MMP)‑2 and MMP‑9. In conclusion, COL6A1 and COL6A2 may act as classical collagens by forming a physical barrier to inhibit BCa tumor growth and invasion.

View Figures

View References

1	Chavan S, Bray F, Lortet-Tieulent J, Goodman M and Jemal A: International variations in bladder cancer incidence and mortality. Eur Urol. 66:59–73. 2014. View Article : Google Scholar : PubMed/NCBI
2	Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, Newling DW and Kurth K: Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 49:466–477. 2006. View Article : Google Scholar : PubMed/NCBI
3	Shariat SF, Karakiewicz PI, Palapattu GS, Lotan Y, Rogers CG, Amiel GE, Vazina A, Gupta A, Bastian PJ, Sagalowsky AI, et al: Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: A contemporary series from the Bladder Cancer Research Consortium. J Urol. 176(6 Pt 1): 2414–2422. 2006. View Article : Google Scholar : PubMed/NCBI
4	Tilki D, Reich O, Karakiewicz PI, Novara G, Kassouf W, Ergün S, Fradet Y, Ficarra V, Sonpavde G, Stief CG, et al: Validation of the AJCC TNM substaging of pT2 bladder cancer: Deep muscle invasion is associated with significantly worse outcome. Eur Urol. 58:112–117. 2010. View Article : Google Scholar : PubMed/NCBI
5	Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 507:315–322. 2014. View Article : Google Scholar : PubMed/NCBI
6	Lee JY, Yun SJ, Jeong P, Piao XM, Kim YH, Kim J, Subramaniyam S, Byun YJ, Kang HW, Seo SP, et al: Identification of differentially expressed miRNAs and miRNA-targeted genes in bladder cancer. Oncotarget. 9:27656–27666. 2018. View Article : Google Scholar : PubMed/NCBI
7	Piao XM, Jeong P, Kim YH, Byun YJ, Xu Y, Kang HW, Ha YS, Kim WT, Lee JY, Woo SH, et al: Urinary cell-free microRNA biomarker could discriminate bladder cancer from benign hematuria. Int J Cancer. 144:380–388. 2019. View Article : Google Scholar
8	Joyce JA and Pollard JW: Microenvironmental regulation of metastasis. Nat Rev Cancer. 9:239–252. 2009. View Article : Google Scholar : PubMed/NCBI
9	Venning FA, Wullkopf L and Erler JT: Targeting ECM disrupts cancer progression. Front Oncol. 5:2242015. View Article : Google Scholar : PubMed/NCBI
10	Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, et al: Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 139:891–906. 2009. View Article : Google Scholar : PubMed/NCBI
11	Arnold SA, Rivera LB, Miller AF, Carbon JG, Dineen SP, Xie Y, Castrillon DH, Sage EH, Puolakkainen P, Bradshaw AD and Brekken RA: Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Models Mech. 3:57–72. 2010. View Article : Google Scholar
12	Aitken KJ and Bägli DJ: The bladder extracellular matrix. Part I: Architecture, development and disease. Nat Rev Urol. 6:596–611. 2009. View Article : Google Scholar : PubMed/NCBI
13	Cescon M, Gattazzo F, Chen P and Bonaldo P: Collagen VI at a glance. J Cell Sci. 128:3525–3531. 2015. View Article : Google Scholar : PubMed/NCBI
14	Wan F, Wang H, Shen Y, Zhang H, Shi G, Zhu Y, Dai B and Ye D: Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients. Oncotarget. 6:27378–27387. 2015. View Article : Google Scholar : PubMed/NCBI
15	Zhu YP, Wan FN, Shen YJ, Wang HK, Zhang GM and Ye DW: Reactive stroma component COL6A1 is upregulated in castration-resistant prostate cancer and promotes tumor growth. Oncotarget. 6:14488–14496. 2015. View Article : Google Scholar : PubMed/NCBI
16	Hou T, Tong C, Kazobinka G, Zhang W, Huang X, Huang Y and Zhang Y: Expression of COL6A1 predicts prognosis in cervical cancer patients. Am J Transl Res. 8:2838–2844. 2016.PubMed/NCBI
17	Chiu KH, Chang YH, Wu YS, Lee SH and Liao PC: Quantitative secretome analysis reveals that COL6A1 is a metastasis-associated protein using stacking gel-aided purification combined with iTRAQ labeling. J Proteome Res. 10:1110–1125. 2011. View Article : Google Scholar
18	Stone R II, Sabichi AL, Gill J, Lee IL, Adegboyega P, Dai MS, Loganantharaj R, Trutschl M, Cvek U and Clifford JL: Identification of genes correlated with early-stage bladder cancer progression. Cancer Prev Res (Phila). 3:776–786. 2010. View Article : Google Scholar :
19	Shi S and Tian B: Identification of biomarkers associated with progression and prognosis in bladder cancer via co-expression analysis. Cancer Biomark. 24:183–193. 2019. View Article : Google Scholar : PubMed/NCBI
20	Zhu H, Chen H, Wang J, Zhou L and Liu S: Collagen stiffness promoted non-muscle-invasive bladder cancer progression to muscle-invasive bladder cancer. OncoTargets Ther. 12:3441–3457. 2019. View Article : Google Scholar
21	Oosterlinck W, Lobel B, Jakse G, Malmström PU, Stöckle M and Sternberg C; European Association of Urology (EAU) Working Group on Oncological Urology: Guidelines on bladder cancer. Eur Urol. 41:105–112. 2002. View Article : Google Scholar : PubMed/NCBI
22	Witjes JA, Compérat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG and Sherif A; European Association of Urology: EAU guidelines on muscle-invasive and metastatic bladder cancer: Summary of the 2013 guidelines. Eur Urol. 65:778–792. 2014. View Article : Google Scholar : PubMed/NCBI
23	Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, Hernandez V, Espinós EL, Dunn J, Rouanne M, et al: Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 71:462–475. 2017. View Article : Google Scholar
24	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
25	Yun SJ, Jeong P, Kang HW, Kim YH, Kim EA and Yan C: Urinary MicroRNAs of prostate cancer: Virus-Encoded hsv1-miRH18 and hsv2-miR-H9-5p could be valuable diagnostic markers. Int Neurourol J. 19:74–84. 2015. View Article : Google Scholar : PubMed/NCBI
26	Xiang M, Zeng Y, Yang R, Xu H, Chen Z, Zhong J, Xie H, Xu Y and Zeng X: U6 is not a suitable endogenous control for the quantification of circulating microRNAs. Biochem Biophys Res Commun. 454:210–214. 2014. View Article : Google Scholar : PubMed/NCBI
27	Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, et al: STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47(D1): D607–D613. 2019. View Article : Google Scholar
28	Knowles MA and Hurst CD: Molecular biology of bladder cancer: New insights into pathogenesis and clinical diversity. Nat Rev Cancer. 15:25–41. 2015. View Article : Google Scholar
29	Chen P, Cescon M and Bonaldo P: Collagen VI in cancer and its biological mechanisms. Trends Mol Med. 19:410–417. 2013. View Article : Google Scholar : PubMed/NCBI
30	Jin Z, Yao J, Xie N, Cai L, Qi S, Zhang Z and Li B: Melittin constrains the expression of identified key genes associated with bladder cancer. J Immunol Res. 2018:50381722018. View Article : Google Scholar : PubMed/NCBI
31	Fang M, Yuan J, Peng C and Li Y: Collagen as a double-edged sword in tumor progression. Tumor Biol. 35:2871–2882. 2014. View Article : Google Scholar
32	Otto T and Sicinski P: Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 17:93–115. 2017. View Article : Google Scholar : PubMed/NCBI
33	Jeggo PA, Pearl LH and Carr AM: DNA repair, genome stability and cancer: A historical perspective. Nat Rev Cancer. 16:35–42. 2016. View Article : Google Scholar
34	Shamloo B and Usluer S: p21 in cancer research. Cancers. 11:11782019. View Article : Google Scholar :
35	Donjerkovic D and Scott DW: Regulation of the G1 phase of the mammalian cell cycle. Cell Res. 10:1–16. 2000. View Article : Google Scholar : PubMed/NCBI
36	Kamiyama M, Naguro I and Ichijo H: In vivo gene manipulation reveals the impact of stress-responsive MAPK pathways on tumor progression. Cancer Sci. 106:785–796. 2015. View Article : Google Scholar : PubMed/NCBI
37	Vivanco I and Sawyers CL: The phosphatidylinositol 3-kinase-AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
38	Koul HK, Pal M and Koul S: Role of p38 MAP kinase signal transduction in solid tumors. Genes Cancer. 4:342–359. 2013. View Article : Google Scholar : PubMed/NCBI
39	Zhou BP, Liao Y, Xia W, Spohn B, Lee MH and Hung MC: Cytoplasmic localization of p21 Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol. 3:245–252. 2001. View Article : Google Scholar : PubMed/NCBI
40	Kumar B, Koul S, Petersen J, Khandrika L, Hwa JS, Meacham RB, Wilson S and Koul HK: p38 mitogen-activated protein kinase-driven MAPKAPK2 regulates invasion of bladder cancer by modulation of MMP-2 and MMP-9 activity. Cancer Res. 70:832–841. 2010. View Article : Google Scholar : PubMed/NCBI
41	Chetty C, Lakka SS, Bhoopathi P and Rao JS: MMP-2 alters VEGF expression via alphaVbeta3 integrin-mediated PI3K/AKT signaling in A549 lung cancer cells. Int J Cancer. 127:1081–1095. 2010. View Article : Google Scholar :
42	Giannı̀ M, Kopf E, Bastien J, Oulad-Abdelghani M, Garattini E, Chambon P and Rochette-Egly C: Down-regulation of the phosphatidylinositol 3-kinase/Akt pathway is involved in retinoic acid-induced phosphorylation, degradation, and transcriptional activity of retinoic acid receptor gamma 2. J Biol Chem. 277:24859–24862. 2002. View Article : Google Scholar
43	Liu W, Ding I, Chen K, Olschowka J, Xu J, Hu D, Morrow GR and Okunieff P: Interleukin 1beta (IL1B) signaling is a critical component of radiation-induced skin fibrosis. Radiat Res. 165:181–191. 2006. View Article : Google Scholar : PubMed/NCBI
44	Wang F, Tang J, Li P, Si S, Yu H, Yang X, Tao J, Lv Q, Gu M, Yang H and Wang Z: Chloroquine enhances the radiosensitivity of bladder cancer cells by inhibiting autophagy and activating apoptosis. Cell Physiol Biochem. 45:54–66. 2018. View Article : Google Scholar : PubMed/NCBI
45	Devanand P, Kim SI, Choi YW, Sheen SS, Yim H, Ryu MS, Kim SJ, Kim WJ and Lim IK: Inhibition of bladder cancer invasion by Sp1-mediated BTG2 expression via inhibition of DNA methyltransferase 1. FEBS J. 281:5581–5601. 2014. View Article : Google Scholar : PubMed/NCBI
46	Wu D, Tao J, Xu B, Qing W, Li P, Lu Q and Zhang W: Phosphatidylinositol 3-kinase inhibitor LY294002 suppresses proliferation and sensitizes doxorubicin chemotherapy in bladder cancer cells. Urol Int. 86:346–354. 2011. View Article : Google Scholar : PubMed/NCBI
47	Wahafu W, Gai J, Song L, Ping H, Wang M, Yang F, Niu Y and Xing N: Increased H²S and its synthases in urothelial cell carcinoma of the bladder, and enhanced cisplatin-induced apoptosis following H²S inhibition in EJ cells. Oncol Lett. 15:8484–8490. 2018.PubMed/NCBI
48	Silvers CR, Liu YR, Wu CH, Miyamoto H, Messing EM and Lee YF: Identification of extracellular vesicle-borne periostin as a feature of muscle-invasive bladder cancer. Oncotarget. 7:23335–23345. 2016. View Article : Google Scholar : PubMed/NCBI