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Correlation of PPM1A Downregulation with CYP3A4 Repression in the Tumor Liver Tissue of Hepatocellular Carcinoma Patients

  • Patrick C. Flannery
  • Kodye L. Abbott
  • Satyanarayana R. PondugulaEmail author
Short Communication

Abstract

Background and Objective

In many patients with hepatocellular carcinoma (HCC), cytochrome P450 3A4 (CYP3A4) expression has been reported to be significantly reduced in the tumor liver tissue. Moreover, this CYP3A4 repression is associated with decreased CYP3A4-mediated drug metabolism in the tumor liver tissue. However, the underlying mechanisms of CYP3A4 repression are not fully understood. We have previously shown that Mg2+/Mn2+-dependent phosphatase 1A (PPM1A) positively regulates human pregnane X receptor (hPXR)-mediated CYP3A4 expression in a PPM1A expression-dependent manner. We sought to determine whether PPM1A expression is downregulated and whether PPM1A downregulation is correlated with CYP3A4 repression in the tumor liver tissue of HCC patients.

Methods

Quantitative RT-PCR and western blot analyses were performed to study mRNA and protein expression, respectively. Cell-based reporter gene assays were conducted to examine the hPXR transactivation of CYP3A4 promoter activity.

Results

Arginase-1 and glypican-3 gene expression studies confirmed that the tumor samples used in our study originate from HCC livers but not non-hepatocellular tumors. mRNA and protein expression of PPM1A and CYP3A4 was found to be significantly repressed in the tumor liver tissues compared to the matched non-tumor liver tissues. In the reporter gene assays, elevated PPM1A levels counteracted the inhibition of hPXR-mediated CYP3A4 promoter activity by signaling pathways that are upregulated in HCC, suggesting that decreased PPM1A levels in HCC could not fully counteract the hPXR-inhibiting signaling pathways.

Conclusions

Together, these results are consistent with the conclusion that PPM1A downregulation in the tumor liver tissue of HCC patients correlates with CYP3A4 repression. Downregulation of PPM1A levels in the tumor liver tissue may contribute to reduced hPXR-mediated CYP3A4 expression, and provide a novel mechanism of CYP3A4 repression in the tumor liver tissue of HCC patients.

Notes

Acknowledgements

The authors thank Drs. Elaine S. Coleman, Mahmoud Mansour, and Ya-Xiong Tao for sharing their research facilities. The authors also thank Julia M. Salamat for her assistance with western blot analysis.

Compliance with Ethical Standards

Funding

This work was supported by the Animal Health and Disease Research Grant, Auburn University Intramural Grant, and Auburn University Research Initiative in Cancer Grant to Pondugula SR.

Conflict of interest

The authors have declared that no conflict of interest exists.

Supplementary material

13318_2019_595_MOESM1_ESM.pdf (253 kb)
Supplementary material 1 (PDF 253 kb)

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Anatomy, Physiology and Pharmacology, College of Veterinary MedicineAuburn UniversityAuburnUSA
  2. 2.Auburn University Research Initiative in CancerAuburn UniversityAuburnUSA

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