Top

Published in:

01-05-2017 | Original Article

Expression of Rab5a correlates with tumor progression in pancreatic carcinoma

Authors: Yuandong Li, Xiaofang Sun, Donghui Ji, Xiangshun Kong, Dengxiang Liu, Zhenya Zhao, Jingbo Yan, Shubo Chen

Published in: Virchows Archiv | Issue 5/2017

Abstract

Rab family protein Rab5a has been implicated in cancer progression. To date, its expression pattern in human pancreatic cancer has not been investigated. This study aims to examine clinical significance, biological role, and potential mechanism of action of mRab5a in human pancreatic cancer. We analyzed Rab5a protein in cancer tissue of 111 cases of pancreatic cancer using immunohistochemistry. The results show that Rab5a overexpression correlates with high T stage, positive nodal status, and advanced TNM stage. We performed knockdown of Rab5a through transfection of Rab5a-specific siRNA in the Capan-2 cell line, which shows high endogenous expression, and of Rab5a plasmid in the CFPAC-1 cell line, which shows low endogenous expression. Rab5a knockdown inhibited cell proliferation and invasion while its overexpression promoted cell proliferation and invasion. In addition, overexpression of Rab5a induced resistance to 5-FU and gemcitabine while its knockdown reduced resistance to 5-FU and gemcitabine. Furthermore, our results show that Rab5a overexpression upregulates Wnt signaling and expression of Wnt target genes including c-myc and MMP7. Blocking Wnt signaling abolished the effects of Rab5a on Wnt targets and on cancer cell proliferation. In summary, our results show that Rab5a is overexpressed in pancreatic cancer and promotes aggressive biological behavior through regulation of the Wnt/β-catenin signaling pathway.

Available only for authorised users

Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29CrossRefPubMed

Pereira-Leal JB, Seabra MC (2001) Evolution of the Rab family of small GTP-binding proteins. J Mol Biol 313(4):889–901CrossRefPubMed

Stenmark H, Olkkonen VM (2001) The Rab GTPase family. Genome Biol 2(5) REVIEWS3007

Chia WJ, Tang BL (2009) Emerging roles for Rab family GTPases in human cancer. Biochim Biophys Acta 1795(2):110–116PubMed

Cheng KW, Lahad JP, Gray JW, Mills GB (2005) Emerging role of RAB GTPases in cancer and human disease. Cancer Res 65(7):2516–2519CrossRefPubMed

Zhao Z, Liu XF, Wu HC, Zou SB, Wang JY, Ni PH, Chen XH, Fan QS (2010) Rab5a overexpression promoting ovarian cancer cell proliferation may be associated with APPL1-related epidermal growth factor signaling pathway. Cancer Sci 101(6):1454–1462CrossRefPubMed

Pan Y, Wang R, Zhang F, Chen Y, Lv Q, Long G, Yang K (2015) MicroRNA-130a inhibits cell proliferation, invasion and migration in human breast cancer by targeting the RAB5A. Int J Clin Exp Pathol 8(1):384–393PubMedPubMedCentral

Yang PS, Yin PH, Tseng LM, Yang CH, Hsu CY, Lee MY, Horng CF, Chi CW (2011) Rab5A is associated with axillary lymph node metastasis in breast cancer patients. Cancer Sci 102(12):2172–2178CrossRefPubMed

Geng D, Zhao W, Feng Y, Liu J (2016) Overexpression of Rab5a promotes hepatocellular carcinoma cell proliferation and invasion via FAK signaling pathway. Tumour Biol 37(3):3341–3347CrossRefPubMed

10.

Liu SS, Chen XM, Zheng HX, Shi SL, Li Y (2011) Knockdown of Rab5a expression decreases cancer cell motility and invasion through integrin-mediated signaling pathway. J Biomed Sci 18:58CrossRefPubMedPubMedCentral

11.

Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P (1998) Beger H G, and Korc M, increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 55(4):363–369CrossRefPubMed

12.

Kornmann M, Arber N, Korc M (1998) Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum. J Clin Invest 101(2):344–352CrossRefPubMedPubMedCentral

13.

Lin CJ, Malina A, Pelletier J (2009) C-myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. Cancer Res 69(19):7491–7494CrossRefPubMed

14.

Shukla SK, Gunda V, Abrego J, Haridas D, Mishra A, Souchek J, Chaika NV, Yu F, Sasson AR, Lazenby AJ et al (2015) MUC16-mediated activation of mTOR and c-myc reprograms pancreatic cancer metabolism. Oncotarget 6(22):19118–19131CrossRefPubMedPubMedCentral

15.

Koenig A, Linhart T, Schlengemann K, Reutlinger K, Wegele J, Adler G, Singh G, Hofmann L, Kunsch S, Buch T et al (2010) NFAT-induced histone acetylation relay switch promotes c-myc-dependent growth in pancreatic cancer cells. Gastroenterology 138(3):1189–99 e1-2CrossRefPubMed

16.

Kumar K, Raza SS, Knab LM, Chow CR, Kwok B, Bentrem DJ, Popovic R, Ebine K, Licht JD, Munshi HG (2015) GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1. Sci Rep 5:9489CrossRefPubMedPubMedCentral

17.

Kim DY, Kim MJ, Kim HB, Lee JW, Bae JH, Kim DW, Kang CD, Kim SH (2011) Suppression of multidrug resistance by treatment with TRAIL in human ovarian and breast cancer cells with high level of c-myc. Biochim Biophys Acta 1812(7):796–805CrossRefPubMed

18.

McNeil CM, Sergio CM, Anderson LR, Inman CK, Eggleton SA, Murphy NC, Millar EK, Crea P, Kench JG, Alles MC et al (2006) C-myc overexpression and endocrine resistance in breast cancer. J Steroid Biochem Mol Biol 102(1–5):147–155CrossRefPubMed

19.

Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L, Fearon ER, Ljungman M, Simeone DM (2009) Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell 15(3):207–219CrossRefPubMedPubMedCentral

20.

Pilarsky C, Ammerpohl O, Sipos B, Dahl E, Hartmann A, Wellmann A, Braunschweig T, Lohr M, Jesenofsky R, Friess H et al (2008) Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling. J Cell Mol Med 12(6B):2823–2835CrossRefPubMedPubMedCentral

21.

Zhou W, Li Y, Gou S, Xiong J, Wu H, Wang C, Yan H, Liu T (2015) MiR-744 increases tumorigenicity of pancreatic cancer by activating Wnt/beta-catenin pathway. Oncotarget 6(35):37557–37569PubMedPubMedCentral

22.

Wang B, Zou Q, Sun M, Chen J, Wang T, Bai Y, Chen Z, Chen B, Zhou M (2014) Reversion of trichostatin a resistance via inhibition of the Wnt signaling pathway in human pancreatic cancer cells. Oncol Rep 32(5):2015–2022PubMed

23.

Cui J, Jiang W, Wang S, Wang L, Xie K (2012) Role of Wnt/beta-catenin signaling in drug resistance of pancreatic cancer. Curr Pharm Des 18(17):2464–2471CrossRefPubMed

Title: Expression of Rab5a correlates with tumor progression in pancreatic carcinoma
Authors: Yuandong Li
Xiaofang Sun
Donghui Ji
Xiangshun Kong
Dengxiang Liu
Zhenya Zhao
Jingbo Yan
Shubo Chen
Publication date: 01-05-2017
Publisher: Springer Berlin Heidelberg
Published in: Virchows Archiv / Issue 5/2017
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-017-2098-y

At a glance: The STEP trials

Springer Medicine

Expression of Rab5a correlates with tumor progression in pancreatic carcinoma

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2017

In this issue

The relationship between breast cancer molecular subtypes and mast cell populations in tumor microenvironment

A new method for real-time evaluation of pepsin digestion of paraffin-embedded tissue sections, prior to fluorescence in situ hybridisation

Histopathological findings of extra-ileal manifestations at initial diagnosis of Crohn’s disease-related ileitis

Overexpression of Rsf-1 correlates with poor survival and promotes invasion in non-small cell lung cancer

Pathology of infectious diseases: what does the future hold?