FGFR2 Promotes Gastric Cancer Progression by Inhibiting the Expression of Thrombospondin4 via PI3K-Akt-Mtor Pathway

Abstract

Background/Aims: Fibroblast growth factor receptor 2 (FGFR2) has attracted considerable interest as a therapeutic target in gastric cancer (GC). There is growing evidence to suggest that the bioavailability of the potent pro-tumor function of FGFR2 is associated with thrombospondins (TSPs). As a follow-on from our previous study, here we evaluated the potential clinical significance and mechanism of the relationship between FGFR2 and TSP4 in GC. Methods: Expression levels of FGFR2 and TSP4 were detected by immunohistochemistry in GC tissue microarray slides. SGC7901 and MKN28 cell lines were used to confirm the relationship between FGFR2 and TSP4. In vitro cell viability, colony formation, and invasion and migration assays were performed to evaluate the effect of FGFR2-TSP4 axis on tumor cell activities. The mechanism of TSP4 regulated by FGFG2 was explored via small molecular inhibitors in vitro and a xenograft model. Results: FGFR2 was shown to be markedly overexpressed in GC tissues and was correlated with a high risk of lymph node metastasis, late clinical stage, and poor prognosis. Low TSP4 expression was associated with shorter overall survival (OS) and advanced stage in GC patients. Interestingly, correlation analysis indicated that FGFR2 was negatively associated with TSP4. Indeed, in vitro and in vivo experiments suggested FGFR2 activation could downregulate TSP4 expression, which played an important role in the proliferation, invasion and migration of GC cells. We also found involvement of the PI3K-AKT-mTOR pathway in the FGFR2-TSP4 axis. Conclusion: The FGFR2 signal promotes human GC progression through the downregulation of TSP4 via PI3K-AKT-mTOR pathway. Our findings provide a foundation for further investigating promising therapeutic strategies for GC overexpressing FGFR2.

Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis

“…Huang et al recently suggested that FGFR2 signaling promotes GC by regulating the expression of Thrombospondin 1 (THBS1) and THBS4 via the PI3K-Akt-mTOR pathway. They indicated that FGF7-FGFR2 signaling upregulates THBS1, while THBS4 is decreased by the FGFR2-Akt cascade [80,89]. These studies established that PI3K-Akt signaling partially contributes to the tumor-promoting function of FGFR2 in GC, although the contribution of the THBS family to GC is still not fully understood.…”

Network-based identification of biomarkers for colon adenocarcinoma

“…Some of the 12 functional genes have been connected with COAD or other diseases according to the existing research. For example, TPM2 was reported to be in implicated in CRC [ 60 ]; STMN2 might be involved in beta-catenin/TCF-mediated carcinogenesis in human hepatoma cells [ 61 ]; CHMP4C was identified as a novel molecular target gene for ovarian cancer [ 62 ]; GRIA3 may act as a mediator of tumor progression in pancreatic cancer [ 63 ]; WDR1 was reported as a therapeutic target in lung cancer [ 64 ]; CPT2 was identified as a potential diagnostic biomarker of colon cancer [ 65 ]; Somatic deletion of KDM1A plays role in advanced colorectal cancer stages [ 66 ]; NFE2L1 , also called Nrf1, was found to be associated to high-risk diffuse large B cell lymphoma [ 67 ]; Gatza et al reported that TGFBR3 promotes colon cancer progression [ 68 ]; FGFR2 was shown to promote gastric cancer progression [ 69 ]. Therefore, the 12 functional genes probably play important roles in COAD and could be the potential prognosis biomarkers for COAD.…”

MicroRNA-559 restrains gastric cancer progression via activating AKT signaling pathway by targeting TRIM14

“…The AKT signaling pathway is one of the most common proliferation pathways in many cancers [37]. It is well known that dysregulation of the AKT signaling pathway is refered to tumorigenesis and progression, such as liver, lung, breast, thyroid, prostate, bladder, pancreatic, gastric, colorectal and cervical cancers [38,39]. It is reported that the various clinicopathological characteristics of cancers are closely related to the activation of AKT signaling pathway [40].…”