Overexpression of Rictor protein and Rictor-H. pylori interaction has impact on tumor progression and prognosis in patients with gastric cancer
Abstract
Introduction. Growing evidence indicates that Rictor (Rapamycin-insensitive companion of mTOR) is overexpressed across several malignancies and associated with poor survival. However, only limited data indicate that Rictor plays a role in gastric cancer (GC). We sought to explore the prognostic value of Rictor in GC and present interaction analysis between Rictor expression and H. pylori status regarding their effects over the prognosis of GC patient.
Materials and methods. 250 GC tissues and 124 lymph node metastases were collected for the detection of Rictor by immunohistochemistry. Cox regression model was used to assess the association between Rictor expression and patient prognosis. Functional experiments were examined in transfected cells using Rictor siRNA. Additive and multiplicative interactions of Rictor and H. pylori were evaluated.
Results. In this study, the positive rate of Rictor was 51.6% (129/150) in GC tissues. Multivariate analyses showed that Rictor was independent unfavorable predictor for OS (HR = 1.554, 95% CI = 1.076–2.244, P = 0.019) and DFS (HR = 1.556, 95% CI = 1.081–2.240, P = 0.017). Patients with upregulated Rictor in the primary tumor and lymph node metastases had the worst prognosis. We observed significant additive and multiplicative interactions between Rictor expression and H. pylori status for OS and DFS (P < 0.05). Our in vitro experiment showed that knockdown of Rictor could suppress cell proliferation, induce apoptosis and inhibit tumor migration and invasion.
Conclusion. Our results demonstrate that Rictor, acting as an oncogene, might be a potential prognostic biomarker and therapeutic target in GC. We suggest that Rictor expression and H. pylori status may be a prognostic marker in gastric cancer.
Keywords: gastric cancerRictorH. pyloriprognosisprogressionIHCsiRNA
References
- Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394–424.
- Toiyama Y, Tanaka K, Kitajima T, et al. Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients. Carcinogenesis. 2015; 36(12): 1474–1483.
- Yuan DD, Zhu ZX, Zhang X, et al. Targeted therapy for gastric cancer: Current status and future directions (Review). Oncol Rep. 2016; 35(3): 1245–1254.
- Betz C, Hall MN. Where is mTOR and what is it doing there? J Cell Biol. 2013; 203(4): 563–574.
- Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007; 12(1): 9–22.
- Sarbassov DD, Ali SM, Kim DH, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004; 14(14): 1296–1302.
- Li H, Lin J, Wang X, et al. Targeting of mTORC2 prevents cell migration and promotes apoptosis in breast cancer. Breast Cancer Res Treat. 2012; 134(3): 1057–1066.
- Wang X, Lai P, Zhang Z, et al. Targeted inhibition of mTORC2 prevents osteosarcoma cell migration and promotes apoptosis. Oncol Rep. 2014; 32(1): 382–388.
- Jiang WJ, Feng RX, Liu JT, et al. RICTOR expression in esophageal squamous cell carcinoma and its clinical significance. Med Oncol. 2017; 34(3): 32.
- Bian Y, Wang Z, Xu J, et al. Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer. Biochem Biophys Res Commun. 2015; 464(2): 534–540.
- Wen SY, Li CH, Zhang YL, et al. Rictor is an independent prognostic factor for endometrial carcinoma. Int J Clin Exp Pathol. 2014; 7(5): 2068–2078.
- Wang F, Sun GP, Zou YF, et al. Helicobacter pylori infection predicts favorable outcome in patients with gastric cancer. Curr Oncol. 2013; 20(5): e388–e395.
- Meimarakis G, Winter H, Assmann I, et al. Helicobacter pylori as a prognostic indicator after curative resection of gastric carcinoma: a prospective study. The Lancet Oncology. 2006; 7(3): 211–222.
- Li Na, Tang B, Jia YP, et al. CagA Protein Negatively Regulates Autophagy and Promotes Inflammatory Response via c-Met-PI3K/Akt-mTOR Signaling Pathway. Front Cell Infect Microbiol. 2017; 7: 417.
- Hu G, Guo L, Ye G. Helicobacter pylori infection impairs gastric epithelial barrier function via microRNA‑100‑mediated mTOR signaling inhibition. Mol Med Rep. 2018; 18(1): 587–594.
- Marrelli D, Pinto E, Stefano ADe, et al. Clinical utility of CEA, CA 19-9, and CA 72-4 in the follow-up of patients with resectable gastric cancer. Am J Surg. 2001; 181(1): 16–19.
- Gulhati P, Cai Q, Li J, et al. Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res. 2009; 15(23): 7207–7216.
- Andersson T, Alfredsson L, Källberg H, et al. Calculating measures of biological interaction. Eur J Epidemiol. 2005; 20(7): 575–579.
- Hughes T, Adler A, Kelly JA, et al. BIOLUPUS Network. Evidence for gene-gene epistatic interactions among susceptibility loci for systemic lupus erythematosus. Arthritis Rheum. 2012; 64(2): 485–492.
- Wang F, Liu J, Zou Y, et al. MicroRNA-143-3p, up-regulated in H. pylori-positive gastric cancer, suppresses tumor growth, migration and invasion by directly targeting AKT2. Oncotarget. 2017; 8(17): 28711–28724.
- Roulin D, Cerantola Y, Dormond-Meuwly A, et al. Targeting mTORC2 inhibits colon cancer cell proliferation in vitro and tumor formation in vivo. Mol Cancer. 2010; 9: 57.
- Gulhati P, Bowen KA, Liu J, et al. mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways. Cancer Res. 2011; 71(9): 3246–3256.
- Cui Y, Zhao J, Yi L, et al. microRNA-153 Targets mTORC2 Component Rictor to Inhibit Glioma Cells. PLoS One. 2016; 11(6): e0156915.
- Guan B, Wu K, Zeng J, et al. Tumor-suppressive microRNA-218 inhibits tumor angiogenesis via targeting the mTOR component RICTOR in prostate cancer. Oncotarget. 2017; 8(5): 8162–8172.
- Werfel TA, Wang S, Jackson MA, et al. Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival. Cancer Res. 2018; 78(7): 1845–1858.
- Schmidt KM, Hellerbrand C, Ruemmele P, et al. Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models. Oncotarget. 2017; 8(15): 24491–24505.
- Cheng H, Zou Y, Ross JS, et al. RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors. Cancer Discov. 2015; 5(12): 1262–1270.
- Kim ST, Kim SY, Klempner SJ, et al. Rapamycin-insensitive companion of mTOR (RICTOR) amplification defines a subset of advanced gastric cancer and is sensitive to AZD2014-mediated mTORC1/2 inhibition. Ann Oncol. 2017; 28(3): 547–554.
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