Molecular Biology Reports

, Volume 40, Issue 2, pp 1677–1683 | Cite as

Upregulation of periostin prevents P53-mediated apoptosis in SGC-7901 gastric cancer cells



Periostin is frequently upregulated in human cancers including gastric cancer and implicated in cancer cell proliferation, invasion, and epithelial–mesenchymal transition. This study was undertaken to investigate the effects of periostin overexpression on the chemosensitivity of gastric cancer cells. We constructed a stable cell line overexpressing periostin in SGC-7901 human gastric cancer cells. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that periostin had no influence on the proliferation of SGC-7901 cells. Compared to empty vector-transfected cells, overexpression of periostin rendered SGC-7901 cells more resistant to cisplatin or 5-fluorouracil (5-FU)-induced apoptosis, accompanying with less release of cytochrome c from mitochondria and diminished cleavage of caspase-3 and poly (ADP-ribose) polymerase. Periostin-overexpressing cells treated with cisplatin or 5-FU showed significantly (p < 0.05) decreased expression of Bax and p53 proteins and increased expression of Bcl-2 protein, when compared to drug-treated mock counterparts. Restoration of p53 expression by delivering wild-type p53 gene resulted in a marked increase in drug-induced apoptosis in periostin-overexpressing SGC-7901 cells. Periostin overexpression elevated the phosphorylation of Akt. Pretreatment of periostin-overexpressing cells with an Akt inhibitor, MK-2206, partially rescued periostin-mediated inhibition of p53 expression and drug resistance. Taken together, our data indicate that periostin confers protection against cisplatin or 5-FU-induced apoptosis in SGC-7901 cells, likely through modulating the Akt/p53 pathway, and thus represents a potential therapeutic target in gastric cancer.


Periostin P53 Cisplatin 5-Fluorouracil Akt Chemoresistance 


  1. 1.
    Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M (2005) Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 366:1784–1793PubMedCrossRefGoogle Scholar
  2. 2.
    Kamoshida S, Suzuki M, Shimomura R, Sakurai Y, Komori Y, Uyama I, Tsutsumi Y (2007) Immunostaining of thymidylate synthase and p53 for predicting chemoresistance to S-1/cisplatin in gastric cancer. Br J Cancer 96:277–283PubMedCrossRefGoogle Scholar
  3. 3.
    Marrelli D, De Stefano A, de Manzoni G, Morgagni P, Di Leo A, Roviello F (2005) Prediction of recurrence after radical surgery for gastric cancer: a scoring system obtained from a prospective multicenter study. Ann Surg 241:247–255PubMedCrossRefGoogle Scholar
  4. 4.
    Yonemura Y, Kinoshita K, Fujimura T, Fushida S, Sawa T, Matsuki N, Tanaka S, Kamata T, Takashima T, Miyazaki I (1996) Correlation of the histological effects and survival after neoadjuvant chemotherapy on gastric cancer patients. Hepatogastroenterology 43:1260–1272PubMedGoogle Scholar
  5. 5.
    Yeh KH, Cheng AL (2004) Recent advances in therapy for gastric cancer. J Formos Med Assoc 103:171–185PubMedGoogle Scholar
  6. 6.
    Kim HK, Choi IJ, Kim CG, Kim HS, Oshima A, Michalowski A, Green JE (2011) A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients. PLoS ONE 6:e16694PubMedCrossRefGoogle Scholar
  7. 7.
    Seo JS, Kim TG, Hong YS, Chen JY, Lee SK (2011) Contribution of Epstein-Barr virus infection to chemoresistance of gastric carcinoma cells to 5-fluorouracil. Arch Pharm Res 34:635–643PubMedCrossRefGoogle Scholar
  8. 8.
    Shin HJ, Kim do N, SK Lee (2011) Association between Epstein-Barr virus infection and chemoresistance to docetaxel in gastric carcinoma. Mol Cells 32:173–179PubMedCrossRefGoogle Scholar
  9. 9.
    Yu HG, Ai YW, Yu LL, Zhou XD, Liu J, Li JH, Xu XM, Liu S, Chen J, Liu F, Qi YL, Deng Q, Cao J, Liu SQ, Luo HS, Yu JP (2008) Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer 122:433–443PubMedCrossRefGoogle Scholar
  10. 10.
    Guo X, Ma N, Wang J, Song J, Bu X, Cheng Y, Sun K, Xiong H, Jiang G, Zhang B, Wu M, Wei L (2008) Increased p38-MAPK is responsible for chemotherapy resistance in human gastric cancer cells. BMC Cancer 8:375PubMedCrossRefGoogle Scholar
  11. 11.
    Takeshita S, Kikuno R, Tezuka K, Amann E (1993) Osteoblastspecific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem J 294:271–278PubMedGoogle Scholar
  12. 12.
    Tischler V, Fritzsche FR, Wild PJ, Stephan C, Seifert HH, Riener MO, Hermanns T, Mortezavi A, Gerhardt J, Schraml P, Jung K, Moch H, Soltermann A, Kristiansen G (2010) Periostin is up-regulated in high grade and high stage prostate cancer. BMC Cancer 10:273PubMedCrossRefGoogle Scholar
  13. 13.
    Erkan M, Kleeff J, Gorbachevski A, Reiser C, Mitkus T, Esposito I, Giese T, Buchler MW, Giese NA, Friess H (2007) Periostin creates a tumor-supportive microenvironment in the pancreas by sustaining fibrogenic stellate cell activity. Gastroenterology 132:1447–1464PubMedCrossRefGoogle Scholar
  14. 14.
    Tai IT, Dai M, Chen LB (2005) Periostin induction in tumor cell line explants and inhibition of in vitro cell growth by anti-periostin antibodies. Carcinogenesis 26:908–915PubMedCrossRefGoogle Scholar
  15. 15.
    Gillan L, Matei D, Fishman DA, Gerbin CS, Karlan BY, Chang DD (2002) Periostin secreted by epithelial ovarian carcinoma is a ligand for alpha(V)beta(3) and alpha(V)beta(5) integrins and promotes cell motility. Cancer Res 62:5358–5364PubMedGoogle Scholar
  16. 16.
    Kudo Y, Ogawa I, Kitajima S, Kitagawa M, Kawai H, Gaffney PM, Miyauchi M, Takata T (2006) Periostin promotes invasion and anchorage-independent growth in the metastatic process of head and neck cancer. Cancer Res 66:6928–6935PubMedCrossRefGoogle Scholar
  17. 17.
    Siriwardena BS, Kudo Y, Ogawa I, Kitagawa M, Kitajima S, Hatano H, Tilakaratne WM, Miyauchi M, Takata T (2006) Periostin is frequently overexpressed and enhances invasion and angiogenesis in oral cancer. Br J Cancer 95:1396–1403PubMedCrossRefGoogle Scholar
  18. 18.
    Shao R, Bao S, Bai X, Blanchette C, Anderson RM, Dang T, Gishizky ML, Marks JR, Wang XF (2004) Acquired expression of periostin by human breast cancers promotes tumor angiogenesis through up-regulation of vascular endothelial growth factor receptor 2 expression. Mol Cell Biol 24:3992–4003PubMedCrossRefGoogle Scholar
  19. 19.
    Li JS, Sun GW, Wei XY, Tang WH (2007) Expression of periostin and its clinicopathological relevance in gastric cancer. World J Gastroenterol 13:5261–5266PubMedGoogle Scholar
  20. 20.
    Liu Y, Liu BA (2011) Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin. World J Gastroenterol 17:2674–2680PubMedCrossRefGoogle Scholar
  21. 21.
    Sun C, Zhao X, Xu K, Gong J, Liu W, Ding W, Gou Y, Xia G, Ding Q (2011) Periostin: a promising target of therapeutical intervention for prostate cancer. J Transl Med 9:99PubMedCrossRefGoogle Scholar
  22. 22.
    Ben QW, Jin XL, Liu J, Cai X, Yuan F, Yuan YZ (2011) Periostin, a matrix specific protein, is associated with proliferation and invasion of pancreatic cancer. Oncol Rep 25:709–716PubMedGoogle Scholar
  23. 23.
    Hong L, Sun H, Lv X, Yang D, Zhang J, Shi Y (2010) Expression of periostin in the serum of NSCLC and its function on proliferation and migration of human lung adenocarcinoma cell line (A549) in vitro. Mol Biol Rep 37:2285–2293PubMedCrossRefGoogle Scholar
  24. 24.
    Kyutoku M, Taniyama Y, Katsuragi N, Shimizu H, Kunugiza Y, Iekushi K, Koibuchi N, Sanada F, Oshita Y, Morishita R (2011) Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int J Mol Med 28:181–186PubMedGoogle Scholar
  25. 25.
    Kühn B, del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, Keating MT (2007) Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med 13:962–969PubMedCrossRefGoogle Scholar
  26. 26.
    Ontsuka K, Kotobuki Y, Shiraishi H, Serada S, Ohta S, Tanemura A, Yang L, Fujimoto M, Arima K, Suzuki S, Murota H, Toda S, Kudo A, Conway SJ, Narisawa Y, Katayama I, Izuhara K, Naka T (2012) Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts. Exp Dermatol 21:331–336PubMedCrossRefGoogle Scholar
  27. 27.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136PubMedCrossRefGoogle Scholar
  28. 28.
    Jürgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC (1998) Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 95:4997–5002PubMedCrossRefGoogle Scholar
  29. 29.
    Shen Y, White E (2001) p53-Dependent apoptosis pathways. Adv Cancer Res 82:55–84PubMedCrossRefGoogle Scholar
  30. 30.
    Rasul A, Ding C, Li X, Khan M, Yi F, Ali M, Ma T (2012) Dracorhodin perchlorate inhibits PI3K/Akt and NF-κB activation, up-regulates the expression of p53, and enhances apoptosis. Apoptosiss. doi: 10.1007/s10495-012-0742-1 Google Scholar
  31. 31.
    Zhang Y, Li Q, Ge Y, Chen Y, Chen J, Dong Y, Shi W (2012) Silibinin triggers apoptosis and cell-cycle arrest of SGC7901 cells. Phytother Res. doi: 10.1002/ptr.4733 Google Scholar
  32. 32.
    Michaylira CZ, Wong GS, Miller CG, Gutierrez CM, Nakagawa H, Hammond R, Klein-Szanto AJ, Lee JS, Kim SB, Herlyn M, Diehl JA, Gimotty P, Rustgi AK (2010) Periostin, a cell adhesion molecule, facilitates invasion in the tumor microenvironment and annotates a novel tumor-invasive signature in esophageal cancer. Cancer Res 70:5281–5292PubMedCrossRefGoogle Scholar
  33. 33.
    Downward J (2004) PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol 15:177–182PubMedCrossRefGoogle Scholar
  34. 34.
    Haupt S, Berger M, Goldberg Z, Haupt Y (2003) Apoptosis—the p53 network. J Cell Sci 116:4077–4085PubMedCrossRefGoogle Scholar
  35. 35.
    Bao S, Ouyang G, Bai X, Huang Z, Ma C, Liu M, Shao R, Anderson RM, Rich JN, Wang XF (2004) Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway. Cancer Cell 5:329–339PubMedCrossRefGoogle Scholar
  36. 36.
    Ouyang G, Liu M, Ruan K, Song G, Mao Y, Bao S (2009) Upregulated expression of periostin by hypoxia in non-small-cell lung cancer cells promotes cell survival via the Akt/PKB pathway. Cancer Lett 281:213–219PubMedCrossRefGoogle Scholar
  37. 37.
    Utispan K, Sonongbua J, Thuwajit P, Chau-In S, Pairojkul C, Wongkham S, Thuwajit C (2012) Periostin activates integrin α5β1 through a PI3K/AKT-dependent pathway in invasion of cholangiocarcinoma. Int J Oncol 41:1110–1118PubMedGoogle Scholar
  38. 38.
    Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, Saito M, Fukuda K, Nishiyama T, Kitajima S, Saga Y, Fukayama M, Sata M, Kudo A (2008) Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med 205:295–303PubMedCrossRefGoogle Scholar
  39. 39.
    Li G, Oparil S, Sanders JM, Zhang L, Dai M, Chen LB, Conway SJ, McNamara CA, Sarembock IJ (2006) Phosphatidylinositol-3-kinase signaling mediates vascular smooth muscle cell expression of periostin in vivo and in vitro. Atherosclerosis 188:292–300PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  1. 1.Department of Gastroenterology, The First Affiliated HospitalJilin UniversityJilinChina
  2. 2.Department of Gastroenterology, The Fourth Affiliated HospitalHarbin Medical UniversityHarbinChina
  3. 3.Department of Gastroenterology, The Affiliated HospitalGuilin Medical CollegeGuilinChina

Personalised recommendations