Low expression of LACTB promotes tumor progression and predicts poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major life-threatening malignancy worldwide. HCC has an unfavorable prognosis, mainly due to late diagnosis, early metastasis, and post-surgical recurrence. Recent studies have demonstrated that beta-lactamases (LACTB) plays a pivotal role in the pathogenesis and progression of several malignant tumors, but its expression and functional role in HCC has not been reported. In this study, we explored the expression of LACTB using The Cancer Genome Atlas datasets and two independent tissues microarrays. We then analyzed the correlation between LACTB expression and clinical outcomes in HCC. We demonstrated that LACTB mRNA and protein levels were both down-regulated in HCC, and decreased LACTB expression was associated with TNM stage, histologic grade, and overall survival of patients. Additionally, through Gene Set Enrichment Analysis, we found that the genes negatively related to the survival of HCC patients were enriched in the low LACTB expression group. Furthermore, we confirmed that overexpression of LACTB inhibited HCC cell proliferation, invasion, and migration in vitro, as well as decreased tumor growth in vivo. Online prediction results suggested that the LACTB gene was markedly correlated with genes involved in the lipid metabolism pathway. In conclusion, these findings suggest that down-regulated LACTB could function as a novel biomarker for diagnosis and prognosis prediction, and LACTB could serve as a promising target in HCC therapy.

[1]  Qiang Liu,et al.  Overexpression of LACTB, a Mitochondrial Protein That Inhibits Proliferation and Invasion in Glioma Cells. , 2019, Oncology research.

[2]  Z. Ren,et al.  CD44 is overexpressed and correlated with tumor progression in gallbladder cancer , 2018, Cancer management and research.

[3]  S. Gautam,et al.  A collagen domain–derived short adiponectin peptide activates APPL1 and AMPK signaling pathways and improves glucose and fatty acid metabolisms , 2018, The Journal of Biological Chemistry.

[4]  F. He,et al.  Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression , 2018, Nature Communications.

[5]  Peng Huang,et al.  PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism. , 2018, Cancer research.

[6]  R. Steuer,et al.  The Circadian Clock Regulates Metabolic Phenotype Rewiring Via HKDC1 and Modulates Tumor Progression and Drug Response in Colorectal Cancer , 2018, EBioMedicine.

[7]  E. Coccia,et al.  Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth , 2018, Proceedings of the National Academy of Sciences.

[8]  Yu-qin Pan,et al.  LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation , 2018, Oncogene.

[9]  X. Li,et al.  KLF4 suppresses the migration of hepatocellular carcinoma by transcriptionally upregulating monoglyceride lipase. , 2018, American journal of cancer research.

[10]  Juan Li,et al.  LDHA is a direct target of miR‐30d‐5p and contributes to aggressive progression of gallbladder carcinoma , 2018, Molecular carcinogenesis.

[11]  J. Yun,et al.  Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma , 2018, Cancer management and research.

[12]  Juan Li,et al.  Upregulation of miR‐374a promotes tumor metastasis and progression by downregulating LACTB and predicts unfavorable prognosis in breast cancer , 2018, Cancer medicine.

[13]  M. Mino‐Kenudson,et al.  Mutant GNAS drives pancreatic tumorigenesis by inducing PKA-mediated SIK suppression and reprogramming lipid metabolism , 2018, Nature Cell Biology.

[14]  Xuehao Wang,et al.  MiR-3662 suppresses hepatocellular carcinoma growth through inhibition of HIF-1α-mediated Warburg effect , 2018, Cell Death & Disease.

[15]  Angélique Gougelet,et al.  β-catenin-activated hepatocellular carcinomas are addicted to fatty acids , 2018, Gut.

[16]  H. Riezman,et al.  mTORC2 Promotes Tumorigenesis via Lipid Synthesis. , 2017, Cancer cell.

[17]  Y. Dang,et al.  Comprehensive analysis of long non-coding RNA PVT1 gene interaction regulatory network in hepatocellular carcinoma using gene microarray and bioinformatics. , 2017, American journal of translational research.

[18]  R. Chen,et al.  TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway , 2017, Oncogenesis.

[19]  T. Golub,et al.  LACTB is a tumour suppressor that modulates lipid metabolism and cell state , 2017, Nature.

[20]  Jian-Min Yuan,et al.  Dietary fatty acids and risk of hepatocellular carcinoma in the Singapore Chinese health study , 2016, Liver international : official journal of the International Association for the Study of the Liver.

[21]  D. Calvisi,et al.  Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. , 2016, Journal of hepatology.

[22]  Hushan Yang,et al.  CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways. , 2015, Journal of hepatology.

[23]  M. Lalowski,et al.  LACTB is a filament-forming protein localized in mitochondria , 2009, Proceedings of the National Academy of Sciences.

[24]  S. Horvath,et al.  Variations in DNA elucidate molecular networks that cause disease , 2008, Nature.

[25]  J. Tuimala,et al.  Evolution of a family of metazoan active-site-serine enzymes from penicillin-binding proteins: a novel facet of the bacterial legacy , 2008, BMC Evolutionary Biology.

[26]  P. Kinnunen,et al.  Expression and purification of the mitochondrial serine protease LACTB as an N-terminal GST fusion protein in Escherichia coli. , 2006, Protein expression and purification.

[27]  Huajie Cai,et al.  Hsa_circ_0103809 promotes cell proliferation and inhibits apoptosis in hepatocellular carcinoma by targeting miR-490-5p/SOX2 signaling pathway. , 2018, American journal of translational research.

[28]  Juan Fan,et al.  MiR-155 up-regulated by TGF-β promotes epithelial-mesenchymal transition, invasion and metastasis of human hepatocellular carcinoma cells in vitro. , 2017, American journal of translational research.

[29]  Jian Wang,et al.  MicroRNA-423 enhances the invasiveness of hepatocellular carcinoma via regulation of BRMS1. , 2017, American journal of translational research.

[30]  A. Jemal,et al.  Cancer statistics, 2015 , 2015, CA: a cancer journal for clinicians.