PGAM1, regulated by miR-3614-5p, functions as an oncogene by activating transforming growth factor-\u03b2 (TGF-\u03b2) signaling in the progression of non-small cell lung carcinoma

Fangfang Li,Hao Yang,Guangying Cui,Shanshan Chen,Lu Chen,Guojun Zhang,Ping Li,Tiandong Kong,Jiuling Cheng

doi:10.1038/s41419-020-02900-4

Abstract

Phosphoglycerate mutase 1 (PGAM1) is a recently identified key catalytic enzyme in aerobic glycolysis. Recent literature has documented that dysregulated PGAM1 expression is associated with tumorigenesis in various cancers. However, the expression status and biological function of PGAM1 in non-small-cell lung cancer (NSCLC) are poorly elucidated. In this study, we found that PGAM1 was overexpressed in NSCLC tissues and that high expression of PGAM1 was associated with poor prognosis in NSCLC patients. Functionally, gain- and loss-of-function analysis showed that PGAM1 promoted proliferation and invasion in vitro, and facilitated tumor growth in vivo. Mechanistically, the transforming growth factor-β (TGF-β) signaling pathway was also markedly impaired in response to PGAM1 silencing. Additionally, we verified that PGAM1 was inhibited by miR-3614-5p via direct targeting of its 3’-untranslated regions in a hypoxia-independent manner. Furthermore, overexpression of miR-3614-5p attenuated NSCLC cell proliferation and invasion, and these effects could be partially reversed by reintroduction of PGAM1. Conclusively, our results suggest that the miR-3614-5p/PGAM1 axis plays a critical role during the progression of NSCLC, and these findings may provide a potential target for the development of therapeutic strategies for NSCLC patients.

Highlights

Lung cancer is the most prevalent malignant tumor and accounts for approximately 27% of all cancerrelated deaths[1]
A similar result was observed in the The Cancer Genome Atlas (TCGA) (Fig. 1b, c) and several Gene Expression Omnibus (GEO) nonsmall-cell lung cancer (NSCLC) cohorts (Fig. 1d)
To explore the prognostic value of phosphoglycerate mutase 1 (PGAM1), the overall survival (OS) and disease-free survival (DFS) rates were analyzed in TCGA cohorts and three additional independent GEO cohorts

Summary

Introduction

Lung cancer is the most prevalent malignant tumor and accounts for approximately 27% of all cancerrelated deaths[1]. Lung cancer is generally divided into two histological subtypes: small cell lung cancer and nonsmall-cell lung cancer (NSCLC), which accounts for approximately 80% of all lung cancers[2]. Li et al Cell Death and Disease (2020)11:710 expression was associated with reduced patient survival, and PGAM1 silencing suppressed aggressive tumor phenotypes and mTOR-dependent glycolysis of NSCLC cell[11]. Another novel PGAM1 allosteric inhibitor, HKB99, has been reported to suppress tumor growth and metastasis and overcome drug resistance in NSCLC12. The relationship between PGAM1 expression and prognosis in NSCLC and the functional role and regulatory network of PGAM1 remain largely unknown

Methods

Results

Conclusion