Sarco (endo)plasmic reticulum Ca2+-ATPase (SERCAs) 3 is involved in calcium mobilization from endoplasmic reticulum into cytosol and closely links to metabolism, neuronal plasticity, gene transcription, cell growth, differentiation, apoptosis, protein folding, and carcinogenesis. To clarify the role of SERCA3 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry and in situ hybridization (ISH) on tissue microarrays containing gastric carcinomas, adjacent non-neoplastic mucosa (NNM), and metastatic lymph node. SERCA3 expression was studied in gastric carcinoma tissue and cell lines by Western blot, reverse transcriptase-polymerase chain reaction, or immunofluorescence. The results demonstrated that SERCA3 was distinctively expressed in GES-1, AGS, BGC-823, GT-3TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, and STKM-2 at both mRNA and protein levels. The carcinomas showed higher SERCA3 mRNA expression than the matched NNM by real-time PCR and ISH (P < 0.05). Immunohistochemically, SERCA3 expression was decreased from gastric NNM, primary to metastatic carcinoma (P < 0.05). SERCA3 expression was negatively related to depth of invasion, distant metastasis, and tumor node metastasis (TNM) staging (P < 0.05), but not to age, sex, lymphatic or venous invasion, or lymph node metastasis (P > 0.05). Kaplan–Meier analysis indicated that SERCA3 expression was positively associated with favorable prognosis of the patients with gastric carcinoma (P < 0.05). Cox’s proportional hazard model indicated that venous invasion, distant metastasis and TNM staging (P < 0.05) were independent prognostic factors for gastric carcinomas. It was suggested that downregulated SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas. It might be employed to indicate the pathobiological behaviors and prognosis of gastric carcinomas.
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This study was supported by Shenyang Outstanding Talent Foundation of China; Shenyang Science and Technology grant (F11-264-1-10); Natural Scientific Foundation of China (no. 81001093, no. 81101886, no. 81172371); a Project Supported by Scientific Research Fund of Liaoning Provincial Education Department (L2010649); Specialized Research Fund for the Doctoral Program of Higher Education (no. 20102104120026) and Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports and Technology of Japan (23659958).
Arbabian A, Brouland JP, Gélébart P, Kovàcs T, Bobe R, Enouf J, et al. Endoplasmic reticulum calcium pumps and cancer. Biofactors. 2011;37:139–49.PubMedCrossRefGoogle Scholar
Arredouani A, Guiot Y, Jonas JC, Liu LH, Nenquin M, Pertusa JA, et al. SERCA3 ablation does not impair insulin secretion but suggests distinct roles of different sarcoendoplasmic reticulum Ca(2+) pumps for Ca(2+) homeostasis in pancreatic beta-cells. Diabetes. 2002;51:3245–53.PubMedCrossRefGoogle Scholar
Baba-Aïssa F, Raeymaekers L, Wuytack F, Callewaert G, Dode L, Missiaen L, et al. Purkinje neurons express the SERCA3 isoform of the organellar type Ca(2+)-transport ATPase. Brain Res Mol Brain Res. 1996;41:169–74.PubMedCrossRefGoogle Scholar
Brouland JP, Gélébart P, Kovàcs T, Enouf J, Grossmann J, Papp B. The loss of sarco/endoplasmic reticulum calcium transport ATPase 3 expression is an early event during the multistep process of colon carcinogenesis. Am J Pathol. 2005;167:233–42.PubMedCrossRefGoogle Scholar
Brouland JP, Valleur P, Papp B. Expression of SERCA pumps during cell differentiation and tumorigenesis: application to colonic carcinogenesis. Ann Pathol. 2006;26:159–72.PubMedCrossRefGoogle Scholar
Chandrasekera PC, Kargacin ME, Deans JP, Lytton J. Determination of apparent calcium affinity for endogenously expressed human sarco(endo)plasmic reticulum calcium-ATPase isoform SERCA3. Am J Physiol Cell Physiol. 2009;296:C1105–14.PubMedCrossRefGoogle Scholar
Gélébart P, Kovács T, Brouland JP, van Gorp R, Grossmann J, Rivard N, et al. Expression of endomembrane calcium pumps in colon and gastric cancer cells. Induction of SERCA3 expression during differentiation. J Biol Chem. 2002;277:26310–20.PubMedCrossRefGoogle Scholar
Kao J, Fortner CN, Liu LH, Shull GE, Paul RJ. Ablation of the SERCA3 gene alters epithelium-dependent relaxation in mouse tracheal smooth muscle. Am J Physiol Lung Cell Mol Physiol. 1999;277:L264–70.Google Scholar
Kumada T, Tsuneyama K, Hatta H, Ishizawa S, Takano Y. Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol. 2004;17:1141–9.PubMedCrossRefGoogle Scholar
Li W, Murai Y, Okada E, Matsui K, Hayashi S, Horie M, et al. Modified and simplified western blotting protocol: use of intermittent microwave irradiation (IMWI) and 5 % skim milk to improve binding specificity. Pathol Int. 2002;52:234–8.PubMedCrossRefGoogle Scholar
Liu LH, Paul RJ, Sutliff RL, Miller ML, Lorenz JN, Pun RY, et al. Defective endothelium- dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signalling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. J Biol Chem. 1997;272:30538–45.PubMedCrossRefGoogle Scholar
Roe MW, Philipson LH, Frangakis CJ, Kuznetsov A, Mertz RJ, Lancaster ME, et al. Defective glucose-dependent endoplasmic reticulum Ca2+ sequestration in diabetic mouse islets of Langerhans. J Biol Chem. 1994;269:18279–82.PubMedGoogle Scholar
Varadi A, Lebel L, Hashim Y, Mehta Z, Ashcroft SJH, Turner R. Sequence variants of the sarco(endo)plasmic reticulum Ca2+-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK Prospective Diabetes Study 48). Diabetologia. 1999;42:1240–3.PubMedCrossRefGoogle Scholar
Wuytack F, Dode L, Baba-Aissa F, Raeymaekers L. The SERCA3-type of organellar Ca2+ pumps. Biosci Rep. 1995;15:299–306.PubMedCrossRefGoogle Scholar
Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, et al. Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas. Virchows Arch. 2008;452:525–34.PubMedCrossRefGoogle Scholar
Zheng HC, Takahashi H, Li XH, Hara T, Masuda S, Guan YF, et al. Downregulated parafibromin expression is a promising marker for pathogenesis, invasion, metastasis and prognosis of gastric carcinomas. Virchows Arch. 2008;452:147–55.PubMedCrossRefGoogle Scholar
Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, et al. Pathobiological characteristics of intestinal and diffuse-type gastric carcinoma in Japan: an immunostaining study on the tissue microarray. J Clin Pathol. 2007;60:273–7.PubMedCrossRefGoogle Scholar
Zheng HC, Zheng YS, Li XH, Takahashi H, Hara T, Masuda S, et al. Arp2/3 overexpression contributed to pathogenesis, growth and invasion of gastric carcinoma. Anticancer Res. 2008;28:2225–32.PubMedGoogle Scholar