Overexpression of Rictor protein in colorectal cancer is correlated with tumor progression and prognosis

Abstract

Abstract. In order to understand the clinical significance of rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) in colorectal cancer (CRC), 62 CRC tissue samples excised during operations were evaluated by immunohistochemistry. Analysis of the association between the expression level of Rictor protein and clinicopathological parameters demonstrated that the expression level of Rictor in CRC tissues was significantly higher than that in paracarcinoma tissues (P<0.0001). In cellular experiments, this result was further confirmed by comparing differences in Rictor expression between the CRC cell lines HCT116, SW480 and LoVo, and the human normal liver cell line HL-7702. It was also noticed that the expression of Rictor was associated with Dukes stage, lymphatic metastasis and prognosis, as determined by χ 2 test, Kaplan-Meier analysis and log-rank test. These results suggest that Rictor may be a novel target for the treatment and prognostic assessment of CRC patients in the future. IntroductionColorectal cancer (CRC) is the third most commonly diagnosed cancer in the world and its morbidity has increased in recent years (1). Dysregulation of mammalian target of rapamycin (mTOR) and mTOR signaling is frequently observed in a variety of human cancers (2). mTOR exists in two functionally distinct complexes: mTOR complex 1 (mTORC1), containing mTOR and regulatory-associated protein of mTOR, and mTORC2, containing mTOR and rapamycin-insensitive companion of mTOR (Rictor) (3). mTORC1 is sensitive to rapamycin and responds to multiple stimuli, including energy status, growth factors, amino acids and inflammation (4). mTORC2 affects cell morphology and actin polymerization (5,6), and mainly promotes cell proliferation and survival through phosphorylation of Akt and serine/threonine-protein kinases (STK) (7,8). Rictor, which is insensitive to rapamycin, forms mTORC2 by binding to mammalian lethal with SEC13 protein 8, mammalian stress-activated protein kinase interacting protein 1 and protein observed with Rictor (9). Currently, only a limited number of reports indicate that Rictor has certain biological functions in malignant tumors. For example, it has been reported that microRNA (miR)-152 acts as a tumor suppressor by targeting Rictor in gynecological cancers (10). Although Rictor may be involved in cancer progression, its expression in CRC remains unclear.Thus, the present study evaluated the expression levels of Rictor in CRC tissue (experimental group) vs. paracarcinoma tissue (control group) using immunohistochemistry in 62 CRC paraffin-embedded tissue samples excised during operations. The difference in expression was further verified at the cellular level by comparing the differences in the expression level of Rictor between CRC cells and human normal liver cells. The association between the expression levels of Rictor protein and the clinicopathological features of the two groups of patients was compared using the χ 2 test, while the association between the expression of Rictor and the over...

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…mTOR as part of mTORC2 requires the presence of its partners rictor and SIN1 to function. Rictor has been found to be highly expressed in certain types of cancers, such as colorectal cancer and non-small cell lung cancer [208,290]. Therefore, there has been interest in using rictor as a target for cancer therapeutics.…”

TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2

“…A study on TELO2 in CRC demonstrates that a germline mutation of TELO2 regulated the senescence pathway and is related to sessile serrated adenomas and adenocarcinoma progression ( 15 ). Additionally, rapamycin-insensitive companion of mTOR (RICTOR), a specific adaptor of mTORC2 ( 16 ), plays an important role in cancer cell proliferation, autophagy, migration, and invasion via activation of protein kinase B (Akt) ( 17 , 18 ) and is positively correlated with prognosis in CRC ( 19 ). Thus, we hypothesized that TELO2 is important in the development of CRC via mTOR and RICTOR.…”

Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts

“…Mechanistically, it has been reported that heterozygous deletion of ATG5 activated EGFR and Wnt/β–catenin pathways in adenomas of Apc(Min/+) mice leading to the enhancement of the IFN γ-dependent inhibition of these pathways [ 43 ]. Moreover, more recent studies have suggested that the controversial role of ATG5 in CRC might be due to the compensatory activation of autophagy-related proteins (AKT, RICTOR and mTOR) in response to autophagy inhibition [ 44 ], which have also been associated with CRC prognosis [ 45 ]. In contrast to the notion of a role of the ATG5 locus in modulating autophagy, our study has suggested that the ATG5 rs546456 SNP might influence CRC risk by modulating host immune responses.…”