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Cellular Oncology

, Volume 40, Issue 3, pp 219–233 | Cite as

Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression

  • Ramani Gopal
  • Karthikeyan Selvarasu
  • Ponmathi Panneer Pandian
  • Kumaresan GanesanEmail author
Original Paper

Abstract

Purpose

Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations. For the development of novel diagnostic and therapeutic HCC options, a fundamental understanding of the mechanisms associated with the deregulation of candidate genes involved in metabolic perturbation is required.

Methods

A meta-analysis of multiple HCC mRNA profiles was performed to identify consistently deregulated genes. Expression of the acyl-CoA synthetase medium chain family member 3 (ACSM3) gene was subsequently assessed in different HCC tumor stages and correlated with various clinicopathological features. Transcription regulation, survival and pathway-associated features of the ACSM3 gene were investigated using integrative functional genomic and molecular cell biological methods.

Results

We found that expression of the ACSM3 gene was significantly reduced in HCC tissues and was frequently downregulated in patients exhibiting high alpha-fetoprotein (AFP) levels, high alanine aminotransferase (ALT) levels, multiple nodules and large tumors. Loss of ACSM3 expression was found to correlate with advanced HCC stages and a poor survival. In addition, HNF4α was found to positively regulate the expression of the ACSM3 gene, while PPARγ was found to transcriptionally repress it. Downregulation of ACSM3 expression was perceived upon activation of the TGFβ, WNT, AKT and MYC signalling pathways. In addition, we found that ACSM3 expression correlates with fatty acid oxidation in HCC.

Conclusion

Our data provide evidence for a differential expression and regulation of the ACSM3 gene in HCC, and may lay a foundation for therapeutically targeting fatty acid metabolism in these tumors.

Keywords

Hepatocellular carcinoma Meta-analysis Acyl-CoA synthetases ACSM3 HNF4α PPARγ Fatty acid oxidation 

Notes

Acknowledgements

This study was supported by grants from the Department of Atomic Energy (DAE), Government of India (Grant No.6/6/2008/R&D-II-230R) and the Department of Biotechnology (DBT), Government of India (MKU-DBT–IPLS programme, No.BT/PR 14553/INF/22/124/2010). Instrumentation support from UGC-CEGS, DBT-IPLS, UGC-NRCBS, UGC-CAS, and the DST-PURSE programme-supported central facilities of SBS, MKU are greatly acknowledged.

Compliance with ethical standards

Conflict of interest

Conflict of Interest for all authors – None.

Supplementary material

13402_2017_321_MOESM1_ESM.pptx (2.2 mb)
ESM 1 (PPTX 2201 kb)
13402_2017_321_MOESM2_ESM.xlsx (29 kb)
ESM 2 (XLSX 28.8 kb)

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Copyright information

© International Society for Cellular Oncology 2017

Authors and Affiliations

  • Ramani Gopal
    • 1
  • Karthikeyan Selvarasu
    • 1
  • Ponmathi Panneer Pandian
    • 1
  • Kumaresan Ganesan
    • 1
    Email author
  1. 1.Cancer Genetics Laboratory, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological SciencesMadurai Kamaraj UniversityMaduraiIndia

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