Dataset Information

RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation.

ABSTRACT: R-spondin 2 (RSPO2) drives the potentiation of Wnt signaling and is implicated in tumorigenesis in multiple cancers, but its role in ovarian cancer has not been investigated. Here, we reported that RSPO2 promoted the growth and metastasis of ovarian cancer through the activation of FAK/Src signaling cascades. RSPO2 enhanced the autophosphorylation of FAK and Src through a unique dual receptors mechanism. First, RSPO2-LGR4 interaction prevented the endocytic degradation of LGR4 and promoted LGR4-mediated translocation of Src to the plasma membrane. Second, RSPO2 directly bound to integrin β3 as a ligand and enhanced the stability of integrins, and both actions potentiated autoactivation of FAK and/or Src in ovarian cancer cells. RSPO2 expression was increased in ovarian tumors and was associated with poor prognosis in patients. Our study highlights the importance of RSPO2 in ovarian tumor progression and suggests that targeting RSPO2/FAK/Src cascades may constitute potential approaches to inhibit the progression of aggressive ovarian cancer.

SUBMITTER: Pan R

PROVIDER: S-EPMC9547309 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation.

Pan Rulu R Yu Yan Y Zhu Haiyan H Zhang Wenyi W Qin Yuan Y Ye Lin L Dai Juji J Huang Ren R Peng Xinyan X Ye Siqi S Lin Ziqi Z Huang Shishun S Chong Shuyi S Lu Liting L Lu Xincheng X

iScience 20220923 10

R-spondin 2 (RSPO2) drives the potentiation of Wnt signaling and is implicated in tumorigenesis in multiple cancers, but its role in ovarian cancer has not been investigated. Here, we reported that RSPO2 promoted the growth and metastasis of ovarian cancer through the activation of FAK/Src signaling cascades. RSPO2 enhanced the autophosphorylation of FAK and Src through a unique dual receptors mechanism. First, RSPO2-LGR4 interaction prevented the endocytic degradation of LGR4 and promoted LGR4- ...[more]

PMID: 36217544

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Project description:BackgroundMetastasis is one of the leading cause contributes to treatment failure and poor prognosis of hepatocellular carcinoma (HCC) patients. The underlying mechanism of HCC metastasis remains to be determined. Although several RNA binding proteins (RBPs) have been found to participate in tumorigenesis and progression of liver cancer, the role of RBPs in HCC patients with extrahepatic metastases is poorly understood.MethodsBy performing RNA-seq of primary HCC tissues (including HCC with extrahepatic metastasis and those did not develop metastasis), we identified a set of HCC metastasis-associated RBPs candidates. Among which, ribosomal protein S7 (RPS7) was found to be remarkably increased in HCC tissues and be strongly related to HCC poor survival. Overexpression or CRISPR-Cas9-mediated knockout were applied to investigate the role of RPS7 on the metastasis-associated phenotypes of HCC cells. RNA sequencing, RIP, RNA-pull down, dual luciferase reporter assay, nascent RNA capture assay, and RNA decay and so on, were applied to reveal the underlying mechanism of RPS7 induced HCC metastasis.ResultsGain- and loss- of function analyses revealed that RPS7 promoted HCC cells adhesion, migration and invasion capabilities, as well as lung metastasis. Mechanistically, we uncovered that lysyl oxidase-like 2 (LOXL2) was a critical downstream target of RPS7. RPS7 could stabilize LOXL2 mRNA by binding to AUUUA motifs in the 3155-3375 region of the 3'UTR of LOXL2 mRNA, thus increased LOXL2 expression via elevating LOXL2 mRNA abundance. Further research revealed that LOXL2 could accelerate focal adhesion formation through maintaining the protein stability of ITGB1 and activating ITGB1-mediated FAK/SRC signaling pathway, and thereby contribute to the pro-metastasis effect of RPS7.ConclusionsTaken together, our data reveal a novel function of RPS7 in HCC metastasis, also reveal the critical roles of the RPS7/LOXL2/ITGB1 axis in HCC metastasis and shed new light on the exploration of molecular drugs against HCC.

Dataset Information

RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation.

Publications

RSPO2 promotes progression of ovarian cancer through dual receptor-mediated FAK/Src signaling activation.

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