Research Article| Volume 43, ISSUE 4, P837-846, April 2017

Download started.


Decreased REG1α expression suppresses growth, invasion and angiogenesis of bladder cancer

Published:February 02, 2017DOI:



      Previous study has indicated association between REG1α and bladder cancer. The aim of this study was to investigate the role of Regenerating gene I alpha (REG1α) in bladder cancer.


      The role of REG1α in bladder cancer cell proliferation, migration and VEGF-induced angiogenesis was explored in vitro and in vivo. Immunohistochemistry (IHC) analysis was assessed to determine the expression of REG1α in ten paired bladder cancer and adjacent non-cancerous tissues, and in 296 bladder cancer samples.


      Down-regulation of REG1α expression significantly reduced the proliferation, migration, invasion and VEGF-induced angiogenesis in vitro and the growth of xenograft tumors in vivo. VEGF expression in bladder cancer is associated with REG1α expression and recurrence. REG1α was overexpressed in bladder cancer tissues compared with adjacent normal samples. Patients with elevated REG1α exhibited shorter recurrence times and poor survival.


      Downregulation of REG1α expression can reduce tumor growth, migration, invasion and angiogenesis. Our study demonstrates that REG1α can be used as a marker of recurrence and prognosis in bladder cancer. Therefore, REG1α targeting in bladder cancer patients represents a promising therapeutic strategy.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Surgical Oncology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.
        • Naishadham D.
        • Jemal A.
        Cancer statistics, 2013.
        CA Cancer J Clin. 2013; 63: 11-30
        • Quek M.L.
        • Stein J.P.
        • Clark P.E.
        • et al.
        Natural history of surgically treated bladder carcinoma with extravesical tumor extension.
        Cancer. 2003; 98: 955-961
        • Sturgeon C.M.
        • Duffy M.J.
        • Hofmann B.R.
        • et al.
        National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers.
        Clin Chem. 2010; 56: e1-e48
        • Netto G.J.
        • Epstein J.I.
        Theranostic and prognostic biomarkers: genomic applications in urological malignancies.
        Pathology. 2010; 42: 384-394
        • Huang L.P.
        • Savoly D.
        • Sidi A.A.
        • et al.
        CIP2A protein expression in high-grade, high-stage bladder cancer.
        Cancer Med. 2012; 1: 76-81
        • Burger M.
        • Denzinger S.
        • Hartmann A.
        • et al.
        Mcm2 predicts recurrence hazard in stage Ta/T1 bladder cancer more accurately than CK20, Ki67 and histological grade.
        Br J Cancer. 2007; 96: 1711-1715
        • Yamauchi A.
        • Itaya-Hironaka A.
        • Sakuramoto-Tsuchida S.
        • et al.
        Synergistic activations of REG I alpha and REG I beta promoters by IL-6 and Glucocorticoids through JAK/STAT pathway in human pancreatic beta cells.
        J Diabetes Res. 2015; 2015: 173058
        • Takasawa S.
        Regenerating gene (REG) product and its potential clinical usage.
        Expert Opin Ther Targets. 2016; 20: 541-550
        • Geng J.
        • Fan J.
        • Wang P.
        • et al.
        REG1A predicts recurrence in stage Ta/T1 bladder cancer.
        Eur J Surg Oncol. 2009; 35: 852-857
        • Terazono K.
        • Yamamoto H.
        • Takasawa S.
        • et al.
        A novel gene activated in regenerating islets.
        J Biol Chem. 1988; 263: 2111-2114
        • Sekikawa A.
        • Fukui H.
        • Fujii S.
        • et al.
        REG Ialpha protein mediates an anti-apoptotic effect of STAT3 signaling in gastric cancer cells.
        Carcinogenesis. 2008; 29: 76-83
        • Minamiya Y.
        • Kawai H.
        • Saito H.
        • et al.
        REG1A expression is an independent factor predictive of poor prognosis in patients with non-small cell lung cancer.
        Lung Cancer. 2008; 60: 98-104
        • Yuan R.H.
        • Jeng Y.M.
        • Chen H.L.
        • et al.
        Opposite roles of human pancreatitis-associated protein and REG1A expression in hepatocellular carcinoma: association of pancreatitis-associated protein expression with low-stage hepatocellular carcinoma, beta-catenin mutation, and favorable prognosis.
        Clin Cancer Res. 2005; 11: 2568-2575
        • Hayashi K.
        • Motoyama S.
        • Sugiyama T.
        • et al.
        REG Ialpha is a reliable marker of chemoradiosensitivity in squamous cell esophageal cancer patients.
        Ann Surg Oncol. 2008; 15: 1224-1231
        • Sato Y.
        • Motoyama S.
        • Nanjo H.
        • et al.
        REG1A expression status suggests chemosensitivity among advanced thoracic esophageal squamous cell carcinoma patients treated with esophagectomy followed by adjuvant chemotherapy.
        Ann Surg Oncol. 2013; 20: 3044-3051
        • Fujishiro M.
        • Nozawa K.
        • Kawasaki M.
        • et al.
        Regenerating gene (REG) 1 alpha promotes pannus progression in patients with rheumatoid arthritis.
        Mod Rheumatol. 2012; 22: 228-237
        • Hu G.
        • Shen J.
        • Cheng L.
        • et al.
        Reg4 protects against acinar cell necrosis in experimental pancreatitis.
        Gut. 2011; 60: 820-828
        • Nata K.
        • Liu Y.
        • Xu L.
        • et al.
        Molecular cloning, expression and chromosomal localization of a novel human REG family gene, REG III.
        Gene. 2004; 340: 161-170
        • Yoshimoto K.
        • Fujimoto T.
        • Itaya-Hironaka A.
        • et al.
        Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjogren's syndrome.
        Clin Exp Immunol. 2013; 174: 1-9
        • Bishnupuri K.S.
        • Sainathan S.K.
        • Bishnupuri K.
        • et al.
        Reg4-induced mitogenesis involves Akt-GSK3beta-beta-Catenin-TCF-4 signaling in human colorectal cancer.
        Mol Carcinog. 2014; 53: E169-E180
        • Yonemura Y.
        • Sakurai S.
        • Yamamoto H.
        • et al.
        REG gene expression is associated with the infiltrating growth of gastric carcinoma.
        Cancer. 2003; 98: 1394-1400
        • Sekikawa A.
        • Fukui H.
        • Fujii S.
        • et al.
        REG Ialpha protein may function as a trophic and/or anti-apoptotic factor in the development of gastric cancer.
        Gastroenterology. 2005; 128: 642-653
        • Macadam R.C.
        • Sarela A.I.
        • Farmery S.M.
        • et al.
        Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family.
        Br J Cancer. 2000; 83: 188-195
        • Harada K.
        • Zen Y.
        • Kanemori Y.
        • et al.
        Human REG I gene is up-regulated in intrahepatic cholangiocarcinoma and its precursor lesions.
        Hepatology. 2001; 33: 1036-1042
        • Naito Y.
        • Oue N.
        • Hinoi T.
        • et al.
        Reg IV is a direct target of intestinal transcriptional factor CDX2 in gastric cancer.
        PloS One. 2012; 7: e47545
        • Kadowaki Y.
        • Ishihara S.
        • Miyaoka Y.
        • et al.
        Reg protein is overexpressed in gastric cancer cells, where it activates a signal transduction pathway that converges on ERK1/2 to stimulate growth.
        FEBS Lett. 2002; 530: 59-64
        • Lieu H.T.
        • Batteux F.
        • Simon M.T.
        • et al.
        HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice.
        Hepatology. 2005; 42: 618-626
        • Nishimune H.
        • Vasseur S.
        • Wiese S.
        • et al.
        Reg-2 is a motoneuron neurotrophic factor and a signalling intermediate in the CNTF survival pathway.
        Nat Cell Biol. 2000; 2: 906-914
        • Kiji T.
        • Dohi Y.
        • Takasawa S.
        • et al.
        Activation of regenerating gene Reg in rat and human hearts in response to acute stress.
        Am J Physiol Heart Circ Physiol. 2005; 289: H277-H284
        • Takasawa S.
        • Ikeda T.
        • Akiyama T.
        • et al.
        Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration.
        FEBS Lett. 2006; 580: 585-591
        • Kimura M.
        • Naito H.
        • Tojo T.
        • et al.
        REG Ialpha gene expression is linked with the poor prognosis of lung adenocarcinoma and squamous cell carcinoma patients via discrete mechanisms.
        Oncol Rep. 2013; 30: 2625-2631
        • Carmeliet P.
        VEGF as a key mediator of angiogenesis in cancer.
        Oncology. 2005; 69: 4-10
        • Bergers G.
        • Benjamin L.E.
        Tumorigenesis and the angiogenic switch.
        Nat Rev Cancer. 2003; 3: 401-410
        • Hodge D.R.
        • Hurt E.M.
        • Farrar W.L.
        The role of IL-6 and STAT3 in inflammation and cancer.
        Eur J Cancer. 2005; 41: 2502-2512
        • Chen S.H.
        • Murphy D.A.
        • Lassoued W.
        • et al.
        Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.
        Cancer Biol Ther. 2008; 7: 1994-2003