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.

Upregulation of INHBA mediated by the transcription factor BHLHE40 promotes colon cancer cell proliferation and migration

“…INHBA has been implicated in the carcinogenesis along with the progression of numerous cancers, 5–10 including colon cancer. However, its role in colon cancer is unknown.…”

“…6 In lung cancer, INHBA upregulation suppresses Hippo signaling and promotes NSCLC invasion and metastasis. 7 INHBA upregulation in ovarian, 8 esophageal, 9 and colorectal cancer, 10 promotes cancer cell proliferation and migration. These findings indicate that INHBA has oncogenic functions.…”

“…INHBA is also upregulated in gastric cancer and its silencing affects TGF‐β signaling cascade, in turn dampening gastric cancer cell growth, migration along with invasion 6 . In lung cancer, INHBA upregulation suppresses Hippo signaling and promotes NSCLC invasion and metastasis 7 . INHBA upregulation in ovarian, 8 esophageal, 9 and colorectal cancer, 10 promotes cancer cell proliferation and migration.…”

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia

“…Two metalloproteinases, ADAM metallopeptidase domain 19 (ADAM19) and matrix metallopeptidase 9 (MMP9), upregulated under hypoxia, are also associated with cancer progression, mainly through modulation of cell adhesion and migration in several cancers, including NSCLC [70][71][72][73]. Inhibin subunit beta A (INHBA) and SRY-box transcription factor 9 (SOX9) are known to influence cell differentiation and have been reported to increase tumor aggressiveness in NSCLC through induction of epithelial-mesenchymal transition (EMT) [74][75][76][77].…”