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Semaphorin activates Hippo signaling to control cell growth

ABSTRACT: Semaphorins play critical roles in the tumorigenesis of various organs. Originally identified as neuronal axonal guidance molecules and developmental regulators of the nervous and the vascular systems, class 3 Semaphorins (SEMA3s) act through their receptors Plexin As (PLXNAs) and co-receptors Neuropilins (NRPs) to control various processes such as axon growth cone directionality, cell cycle, and angiogenesis. Deletion or silencing of SEMA3B and SEMA3F genes has been observed in lung cancer, metastatic breast cancer, renal carcinoma, and many other malignancies; however, the downstream effectors of SEMA3 in tumorigenesis are still unclear. Here we show that the Hippo pathway is a key mediator of SEMA3’s tumor suppressive function. SEMA3 activates the Hippo pathway to control gene expression and inhibit cell growth. Restoration of SEMA3B expression in lung cancer cells that harbor SEMA3B deletion or silencing suppressed anchorage-independent growth and xenograft formation in a Hippo pathway-dependent manner. Mechanistically, PLXNA promotes the interaction and activation of p190RhoGAPs (ARHGAP5 and ARHGAP35) by the RND GTPase. Activated ARHGAP5/35 in turn act through RhoA and the Hippo kinase cascade to phosphorylate and inactivate YAP and TAZ, the transcriptional co-activators and key effectors of the Hippo pathway. Cancer-associated mutations of RND or ARHGAP5/35 compromised cellular responses to SEMA3, as indicated by YAP phosphorylation and cell growth inhibition. Our study defines a new role of the Hippo pathway in SEMA3 signaling as well as a mechanism for the tumor suppressive function of Semaphorins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139630 | GEO | 2022/06/21

REPOSITORIES: GEO

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Project description:Semaphorins are a large family of evolutionary conserved morphogenetic signals originally identified as repelling cues in axonal guidance. Intriguingly, Semaphorins have recently been implicated to play a role in cancer progression. In particular, Semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. Interestingly, we found that SEMA3B induced the production of Interleukin-8 (IL-8) by tumor cells, by activating p38-MAPK pathway, in a Neuropilin-1 dependent manner. Further, by silencing the expression of endogenous SEMA3B in tumor cells, IL-8 transcription was impaired. The release of IL-8, in turn, induced tumor-associated macrophage recruitment and metastatic dissemination to the lung that could be rescued by using neutralizing antibodies against IL-8. In conclusion, we report here that SEMA3B plays unexpected functions in cancer progression, as it fosters a pro-metastatic environment, through elevated IL-8 secretion and recruitment of macrophages, coupled to suppression of tumor growth. By performing micro-array analysis of gene expression on mRNA derived from MDA-MB-435 cells transduced with SEMA3B or control Empty Vector (EV), we found that one of the most regulated genes was Interleukin-8 (IL-8) (p< 0.001). Interestingly, IL-8 is known to be a chemo-attractant for leucocytes, endothelial and smooth muscle cells, further implicated in human cancer biology. We thus confirmed micro-array data by real-time quantitative PCR in tumor cell lines transduced with SEMA3B: i.e. A549 lung carcinoma, HeLa cervical carcinoma, HT29 colon carcinoma, and GTL16 gastric carcinoma. In addition, western blotting revealed that IL-8 secretion was strongly induced upon SEMA3B expression. Moreover, IL-8 protein levels were specifically up-regulated by treatment with doxycycline in A549 carcinoma cells expressing SEMA3B under control of a drug-inducible promoter. Keywords: Cell type comparison

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Semaphorin activates Hippo signaling to control cell growth

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