Abstract
BackgroundMetabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. MACC1, a transcriptional regulator of MET, was recognized as an oncogene in gastric cancer (GC); however, its transcriptional or post-translational regulation was not clear. We previously reported the metabolic role of MACC1 in glycolysis to promote GC progression. MACC1-AS1 is the antisense lncRNA of MACC1, yet its function was previously unknown.MethodsWe profiled and analyzed the expression of MACC1-AS1 utilizing the TCGA database as well as in situ hybridization using 123 pairs of GC tissues and matched adjacent normal gastric mucosa tissues (ANTs). The biological role of MACC1-AS1 in cell growth and metastasis was determined by performing in vitro and in vivo functional experiments. Glycolysis and antioxidant capabilities were assayed to examine its metabolic function. Further, the specific regulatory effect of MACC1-AS1 on MACC1 was explored transcriptionally and post-transcriptionally.ResultsMACC1-AS1 was shown to be expressed significantly higher in GC tissues than in ANTs, which predicted poor prognosis in GC patients. MACC1-AS1 promoted GC cell proliferation and inhibited cell apoptosis under metabolic stress. Mechanistically, MACC1-AS1 stabilized MACC1 mRNA and post-transcriptionally augmented MACC1 expression. Further, MACC1-AS1 was shown to mediate metabolic plasticity through MACC1 upregulation and subsequent enhanced glycolysis and anti-oxidative capabilities, and this was suggested to be coordinated by the AMPK/Lin28 pathway.ConclusionsElevated expression of MACC1-AS1 in gastric cancer tissues is linked to poor prognosis and promotes malignant phenotype upon cancer cells. MACC1-AS1 is elevated under metabolic stress and facilitates metabolic plasticity by promoting MACC1 expression through mRNA stabilization. Our study implicates lncRNA MACC1-AS1 as a valuable biomarker for GC diagnosis and prognosis.
Highlights
Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis
MACC1-AS1 is upregulated in gastric cancer (GC) tissues and predicts poor prognosis MACC1-AS1 is located on the anti-sense strand of the MACC1 gene; further bioinformatics analysis failed to predict coding probability of more than 0.05 (Additional file 2: Figure S1A-C), supporting the fact that MACC1-AS1 is a lncRNA without protein coding potential
This correlation between MACC1-AS1 and MACC1 was further validated in GC and breast cancer cell lines and compared to that in an immortalized non-cancer cell line (Fig. 1d and Additional file 5: Figure S2A–B)
Summary
Metabolic plasticity has been increasingly thought to be a determinant of tumor growth and metastasis. Metabolic plasticity is considered one of MACC1 is a transcriptional regulator of MET, and has emerged as a master oncogene that is upregulated in a variety of tumors, promoting proliferation, invasion, and chemotherapy resistance [3]. Our previous study demonstrated that MACC1 expression is upregulated and promotes glycolysis under metabolic stress, a state characterized by nutrient deprivation and often occurring in mature tumor tissues due to abnormal vascularization [4, 5]. Antisense lncRNA exerts regulatory effects on the expression of its sense counterpart. This relationship is supported through the analysis of MACC1-AS1 and MACC1 expression using the TCGA database and tumor specimens from patients. We suspected that MACC1-AS1 might regulate MACC1 expression, and the potential mechanism was further explored in this study
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