Hydrogen sulfide modulates epithelial-mesenchymal transition and angiogenesis in non-small cell lung cancer via HIF-1α activation

Abstract

Hydrogen sulfide (H₂S) has been frequently implicated in tumor progression. However, the exact regulation mechanism of H₂S in human non-small cell lung cancer (NSCLC) has not been fully elucidated. Here, analysis of NSCLC biopsies and adjacent non-tumor tissues revealed selectively high levels of endogenous H₂S-producing enzymes, cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). Similarly, quantitative real-time PCR (qRT-PCR) and western blot results showed that NSCLC cell lines (A549, 95D) expressed higher levels of CBS, CSE and MPST in mRNA and enzyme proteins, respectively. Moreover, NSCLC cell lines produced more H₂S than did the normal lung epithelial cell line BEAS-2B. H₂S was further detected to induce NSCLC migration and invasion, as well as the epithelial mesenchymal transition (EMT) process. Small interfering RNA (siRNA) silencing of CBS or CSE activity reduced proliferation and metastasis potential of tumor cells. In addition, H₂S modulated hypoxia-inducible factor-1α (HIF-1α) to stimulate vascular endothelial growth factor (VEGF) expression, which contributes to tumor angiogenesis. Treatment of nude mice with pharmacological inhibition of CBS or CSE activity decreased xenograft growth and suppressed angiogenesis. Collectively, these results indicate H₂S plays an important part in NSCLC growth and angiogenesis by HIF-1α activation, which potentially provide new insight in therapeutic strategies.

Keywords: Angiogenesis; Epithelial-mesenchymal transition; Hydrogen sulfide; Hypoxia-inducible factor-1α; Non-small cell lung cancer.