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FAM98A promotes proliferation of non-small cell lung cancer cells via the P38-ATF2 signaling pathway.

ABSTRACT: FAM98A, a novel protein, is expressed in ovarian and colorectal cancer tissues. However, the association between FAM98A expression and the clinicopathological characteristics of non-small cell lung cancer (NSCLC) remains undetermined.The FAM98A expression pattern was determined in NSCLC samples and corresponding adjacent normal lung tissues using immunohistochemical staining and Western blotting. The association of FAM98A expression with clinicopathological characteristics was measured in 131 NSCLC samples. Finally, the overexpression and inhibition of FAM98A was performed in the A549 and SPC-A1 cell lines to explore its role in the development of lung cancer.Western blot analysis of 20 paired NSCLC samples showed that expression of FAM98A was higher in lung cancer tissues than in the corresponding adjacent normal lung tissues (p<0.05). Immunohistochemical staining of 128 NSCLC specimens showed that expression of FAM98A was significantly higher in lung cancer samples than in adjacent normal lung tissues (118/128 vs 10/128; p<0.001). Positive expression of FAM98A was significantly related to tumor TNM stage (p<0.05) and lymph node metastasis (p<0.001). Additionally, overexpression of FAM98A induced an increase in the expression of phosphorylated P38, phosphorylated ATF2, and cyclin D1, which promoted proliferation of lung cancer cells. Correspondingly, the effects of FAM98A overexpression were reversed by administration of a specific inhibitor of phosphorylated P38.FAM98A was overexpressed in the cytoplasm of NSCLC samples and correlated with advanced TNM staging and lymph node metastasis. Thus, FAM98A increases the expression of cyclin D1 by activating the P38-ATF2 signaling pathway and subsequently enhancing tumor cell proliferation; these results are promising and need further validation.

SUBMITTER: Zheng R

PROVIDER: S-EPMC6067791 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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FAM98A promotes proliferation of non-small cell lung cancer cells via the P38-ATF2 signaling pathway.

Zheng Rui R Liu Quanbo Q Wang Tianxu T Wang Lili L Zhang Yong Y

Cancer management and research 20180727

<h4>Background</h4>FAM98A, a novel protein, is expressed in ovarian and colorectal cancer tissues. However, the association between FAM98A expression and the clinicopathological characteristics of non-small cell lung cancer (NSCLC) remains undetermined.<h4>Materials and methods</h4>The FAM98A expression pattern was determined in NSCLC samples and corresponding adjacent normal lung tissues using immunohistochemical staining and Western blotting. The association of FAM98A expression with clinicopa ...[more]

PMID: 30100758

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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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FAM98A promotes proliferation of non-small cell lung cancer cells via the P38-ATF2 signaling pathway.

Publications

FAM98A promotes proliferation of non-small cell lung cancer cells via the P38-ATF2 signaling pathway.

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