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Inhibin βA is an independent prognostic factor that promotes invasion via Hippo signaling in non‑small cell lung cancer.

ABSTRACT: Inhibin βA (INHBA) serves a prognostic and tumor‑promoting role in numerous types of cancer. The present study aimed to determine the clinical significance of INHBA in non‑small cell lung cancer (NSCLC) and the mechanisms underlying its potential tumor‑promoting effect. INHBA expression was detected in clinical NSCLC samples using immunohistochemistry. In vivo loss‑ and gain‑of‑function studies were performed to determine the effects of INHBA on NSCLC invasion. In addition, protein and mRNA expression levels of INHBA, yes‑associated protein (YAP), large tumor suppressor 1/2 kinase (LATS1/2), connective tissue growth factor, cysteine rich angiogenic inducer 61 and Merlin were assessed using western blotting and reverse transcription‑quantitative PCR, respectively, to investigate the mechanism by which INHBA may affect the invasion of NSCLC. The present study revealed that INHBA was significantly upregulated in 238 clinical NSCLC samples compared with its expression levels in paired adjacent non‑cancerous tissues, and in metastatic nodules compared with in primary tumors. Notably, high INHBA expression was statistically associated with clinicopathological features, including poor differentiation and advanced tumor stage. INHBA positivity was statistically related to decreased 5‑year overall survival, for which INHBA was an independent prognostic factor. Furthermore, INHBA promoted NSCLC invasion in vitro. In NSCLC, INHBA expression was associated with the nuclear levels of YAP and INHBA overexpression enhanced the invasive abilities of NSCLC cells via inhibiting the Hippo pathway. Mechanistically, INHBA inhibited l LATS1/2 phosphorylation and induced YAP nuclear translocation by downregulating the protein expression levels of Merlin. In conclusion, INHBA may negatively regulate the Hippo pathway to act as a tumor promotor, and could represent a marker of prognosis in NSCLC.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8441965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNovel therapeutic targets are urgently needed for treating drug-resistant non-small cell lung cancer (NSCLC) and overcoming drug resistance to molecular-targeted therapies. Regulator of G protein signaling 20 (RGS20) is identified as an upregulated factor in many cancers, yet its specific role and the mechanism through which RGS20 functions in NSCLC remain unclear. Our study aimed to identify the role of RGS20 in NSCLC prognosis and delineate associated cellular and molecular pathways.MethodsImmunohistochemistry and lung cancer tissue microarray were used to verify the expression of RGS20 between NSCLC patients. CCK8 and cell cloning were conducted to determine the proliferation ability of H1299 and Anip973 cells in vitro. Furthermore, Transcriptome sequencing was performed to show enrichment genes and pathways. Immunofluorescence was used to detect the translocation changes of YAP to nucleus. Western blotting demonstrated different expressions of autophagy and the Hippo-PKA signal pathway. In vitro and in vivo experiments verified whether overexpression of RGS20 affect the proliferation and autophagy of NSCLC through regulating the Hippo pathway.ResultsThe higher RGS20 expression was found to be significantly correlated with a poorer five-year survival rate. Further, RGS20 accelerated cell proliferation by increasing autophagy. Transcriptomic sequencing suggested the involvement of the Hippo signaling pathway in the action of RGS20 in NSCLC. RGS20 activation reduced YAP phosphorylation and facilitated its nuclear translocation. Remarkably, inhibiting Hippo signaling with GA-017 promoted cell proliferation and activated autophagy in RGS20 knock-down cells. However, forskolin, a GPCR activator, increased YAP phosphorylation and reversed the promoting effect of RGS20 in RGS20-overexpressing cells. Lastly, in vivo experiments further confirmed role of RGS20 in aggravating tumorigenicity, as its overexpression increased NSCLC cell proliferation.ConclusionOur findings indicate that RGS20 drives NSCLC cell proliferation by triggering autophagy via the inhibition of PKA-Hippo signaling. These insights support the role of RGS20 as a promising novel molecular marker and a target for future targeted therapies in lung cancer treatment.

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Inhibin βA is an independent prognostic factor that promotes invasion via Hippo signaling in non‑small cell lung cancer.

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