Abstract
Previous studies have established the role of phosphorylated form of insulin-like growth factor type 1 receptor (p-IGF1R) as a good candidate for tumor biomarker. The aims of this study were to investigate p-IGF1R expression status in gastric cancer (GC) specimens and to clarify its clinical significance. A total of 78 GC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect p-IGF1R and phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression in paired tumor and adjacent normal tissues. Results showed a higher level of p-IGF1R protein expression in tumor tissues than that in normal tissues, and the rate of p-IGF1R protein high/moderate expression in GC and normal tissues was 52.6 % (41/78) and 6.4 % (5/78), respectively (p < 0.001). In contrast, PTEN protein expression was downregulated in GC, as compared with normal tissues (negative/low expression 49/78 vs. 8/78, p < 0.001). Moreover, PTEN protein downregulation was consistent with p-IGF1R upregulation. Overexpression of p-IGF1R protein was associated with lymph metastasis, clinical stage, and adverse 3-year progression-free survival (PFS). Survival analysis and Cox proportional hazards model revealed that p-IGF1R overexpression was an independent factor in predicting PFS for GC patients, apart from lymph metastasis. In conclusion, p-IGF1R is highly expressed in GC, which may be a novel biomarker to predict the clinical outcome of GC patients.

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Abbreviations
- GC:
-
Gastric cancer
- MAPK:
-
Mitogen-activated protein kinase
- PI3K:
-
Phosphatidylinositol 3-kinase
- PFS:
-
Progression-free survival
- p-IGF1R:
-
Phosphorylated insulin-like growth factor type 1 receptor
- PTEN:
-
Phosphatase and tensin homolog deleted on chromosome ten
References
Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, Malvezzi M, La Vecchia C. Recent patterns in gastric cancer: a global overview. Int J Cancer. 2009;125:666–73.
Zhang H, Sun LL, Meng YL, Song GY, Hu JJ, Lu P, Ji B. Survival trends in gastric cancer patients of Northeast China. World J Gastroenterol. 2011;17:3257–62.
Pietrantonio F, De Braud F, Da Prat V, Perrone F, Pierotti MA, Gariboldi M, Fanetti G, Biondani P, Pellegrinelli A, Bossi I, Di Bartolomeo M. A review on biomarkers for prediction of treatment outcome in gastric cancer. Anticancer Res. 2013;33:1257–66.
Zhang Y, Ye X, Geng J, Chen L. Epigenetic inactivation of deleted in lung and esophageal cancer 1 gene by promoter methylation in gastric and colorectal adenocarcinoma. Hepatogastroenterology. 2010;57:1614–9.
Worrall C, Nedelcu D, Serly J, Suleymanova N, Oprea I, Girnita A, Girnita L. Novel mechanisms of regulation of IGF-1R action: functional and therapeutic implications. Pediatr Endocrinol Rev. 2013;10:473–84.
Chen HX, Sharon E. IGF-1R as an anti-cancer target–trials and tribulations. Chin J Cancer. 2013;32:242–52.
Subramani R, Lopez-Valdez R, Arumugam A, Nandy S, Boopalan T, Lakshmanaswamy R. Targeting insulin-like growth factor 1 receptor inhibits pancreatic cancer growth and metastasis. PLoS ONE. 2014;9:e97016.
Hirakawa T, Yashiro M, Murata A, Hirata K, Kimura K, Amano R, Yamada N, Nakata B, Hirakawa K. IGF-1 receptor and IGF binding protein-3 might predict prognosis of patients with resectable pancreatic cancer. BMC Cancer. 2013;13:392.
Cappuzzo F, Tallini G, Finocchiaro G, Wilson RS, Ligorio C, Giordano L, Toschi L, Incarbone M, Cavina R, Terracciano L, Roncalli M, Alloisio M, Varella-Garcia M, Franklin WA, Santoro A. Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. Ann Oncol. 2010;21:562–7.
Matsubara J, Yamada Y, Hirashima Y, Takahari D, Okita NT, Kato K, Hamaguchi T, Shirao K, Shimada Y, Shimoda T. Impact of insulin-like growth factor type 1 receptor, epidermal growth factor receptor, and HER2 expressions on outcomes of patients with gastric cancer. Clin Cancer Res. 2008;14:3022–9.
Browne BC, Eustace AJ, Kennedy S, O’Brien NA, Pedersen K, McDermott MS, Larkin A, Ballot J, Mahgoub T, Sclafani F, Madden S, Kennedy J, Duffy MJ, Crown J, O’Donovan N. Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours. Breast Cancer Res Treat. 2012;136:717–27.
Wu PF, Huang WC, Yang JC, Lu YS, Shih JY, Wu SG, Lin CH, Cheng AL. Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas. J Neurooncol. 2013;115:61–70.
Wang H, Chen P, Liu XX, Zhao W, Shi L, Gu XW, Zhu CR, Zhu HH, Zong L. Prognostic impact of gastrointestinal bleeding and expression of PTEN and Ki-67 on primary gastrointestinal stromal tumors. World J Surg Oncol. 2014;12:89.
Song H, Xu B, Yi J. Clinical significance of stanniocalcin-1 detected in peripheral blood and bone marrow of esophageal squamous cell carcinoma patients. J Exp Clin Cancer Res. 2012;31:35.
Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4:505–18.
Kornprat P, Rehak P, Rüschoff J, Langner C. Expression of IGF-I, IGF-II, and IGF-IR in gallbladder carcinoma. A systematic analysis including primary and corresponding metastatic tumours. J Clin Pathol. 2006;59(2):202–6.
Zhang C, Hao L, Wang L, Xiao Y, Ge H, Zhu Z, Luo Y, Zhang Y, Zhang Y. Elevated IGFIR expression regulating VEGF and VEGF-C predicts lymph node metastasis in human colorectal cancer. BMC Cancer. 2010;10:184.
Mountzios G, Kostopoulos I, Kotoula V, Sfakianaki I, Fountzilas E, Markou K, Karasmanis I, Leva S, Angouridakis N, Vlachtsis K, Nikolaou A, Konstantinidis I, Fountzilas G. Insulin-like growth factor 1 receptor (IGF1R) expression and survival in operable squamous-cell laryngeal cancer. PLoS ONE. 2013;8:e54048.
Ahlén J, Wejde J, Brosjö O, von Rosen A, Weng WH, Girnita L, Larsson O, Larsson C. Insulin-like growth factor type 1 receptor expression correlates to good prognosis in highly malignant soft tissue sarcoma. Clin Cancer Res. 2005;11:206–16.
Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE, Nicholson RI, Carboni J, Gottardis M, Pollak M, Dunn SE. Phosphorylated insulinlike growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 2008;68:10238–46.
Zhao H, Desai V, Wang J, Epstein DM, Miglarese M, Buck E. Epithelial-mesenchymal transition predicts sensitivity to the dual IGF-1R/IR inhibitor OSI-906 in hepatocellular carcinoma cell lines. Mol Cancer Ther. 2012;11:503–13.
Jones RG, Saibil SD, Pun JM, Elford AR, Bonnard M, Pellegrini M, Arya S, Parsons ME, Krawczyk CM, Gerondakis S, Yeh WC, Woodgett JR, Boothby MR, Ohashi PS. NF-kappaB couples protein kinase B/Akt signaling to distinct survival pathways and the regulation of lymphocyte homeostasis in vivo. J Immunol. 2005;175:3790–9.
Gericke A, Munson M, Ross AH. Regulation of the PTEN phosphatase. Gene. 2006;374:1–9.
Xu WT, Yang Z, Lu NH. Roles of PTEN (phosphatase and tensin homolog) in gastric cancer development and progression. Asian Pac J Cancer Prev. 2014;15:17–24.
Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE. PTEN function: the long and the short of it. Trends Biochem Sci. 2014;39:183–90.
McCampbell AS, Broaddus RR, Loose DS, Davies PJ. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res. 2006;12:6373–8.
Weng LP, Smith WM, Brown JL, Eng C. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet. 2001;10(6):605–16.
Seely BL1, Samimi G, Webster NJ. Retroviral expression of a kinase-defective IGF-I receptor suppresses growth and causes apoptosis of CHO and U87 cells in vivo. BMC Cancer. 2002; 2:15.
Zhao H, Dupont J, Yakar S, Karas M, LeRoith D. PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells. Oncogene. 2004;23:786–94.
Yi HK, Kim SY, Hwang PH, Kim CY, Yang DH, Oh Y, Lee DY. Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun. 2005;330:760–7.
Acknowledgments
This study was supported by National Natural Science Foundation of China (N0. 81101650). The valuable help from the Departments of Pathology of Henan Cancer Hospital, China, is also greatly appreciated.
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Deng, Wy., Li, N., Wan, Xb. et al. Phosphorylated insulin-like growth factor-1 receptor expression predicts poor prognosis of Chinese patients with gastric cancer. Med Oncol 31, 141 (2014). https://doi.org/10.1007/s12032-014-0141-2
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DOI: https://doi.org/10.1007/s12032-014-0141-2