Identification of ABCC3 and its isoforms as potential biomarker in hepatocellular carcinoma

Abstract

Liver diseases preceding the occurrence of hepatocellular carcinoma (HCC) play a crucial role in the progression and establishment of HCC, a malignancy ranked as the third deadliest cancer worldwide. Late diagnosis, alongside ineffective treatment, leads patients to a poor survival rate. This scenario argues for seeking novel alternatives for detecting liver alterations preceding the early occurrence of HCC. Experimental studies have reported that ABCC3 protein increases within HCC tumors but not in adjacent tissue. Therefore, we analyzed ABCC3 expression in public databases and investigated the presence of ABCC3 and its isoforms in plasma, urine and its release in extracellular vesicles (EVs) cargo from patients bearing cirrhosis and HCC. The UALCAN and GEPIA databases were used to analyze the expression of ABCC3 in HCC. The results were validated in a case-control study including 41 individuals bearing cirrhosis and HCC, and the levels of ABCC3 in plasma and urine samples, as well as EVs, were analyzed by ELISA and western blot. Our data showed that ABCC3 expression was higher in HCC tissues than in normal tissues and correlated with HCC grade and stage. ABCC3 protein levels were highly increased in both plasma and urine and correlated with liver disease progression and severity. The isoforms MRP3A and MRP3B of ABCC3 were significantly increased in both EVs and plasma/urine of patients bearing HCC. ABCC3 expression gradually increases in HCC tissues, and its protein levels are increased in both plasma and urine of patients with cirrhosis and HCC. MRP3A and MRP3B isoforms have the potential to be prognostic biomarkers of HCC.

Keywords:

• Chronic liver diseases
• extracellular vesicles
• HCC
• ABCC3
• MRP3

Acknowledgements

We sincerely thank MSc. Adriana Ramirez-Cosmes for her invaluable contribution in collecting and banking the samples. The authors are very thankful to the staff of Hospital General Zona No 1 Dr. Demetrio Mayoral Pardo-IMSS.

Author contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Ethical approval

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the research ethics committee of the ‘Hospital General Zona No 1 Dr. Demetrio Mayoral Pardo-IMSS’ under protocol no. R-2017-785-127, as well as by the ‘Hospital Regional Presidente Juarez-ISSSTE’ under protocol no. 063. All participants provided written informed consent.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets analyzed during this study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was funded by the SS/IMSS/ISSSTE-CONAHCYT Grant No. FOSISSS2017-2-290194, also supported by the CONAHCYT Grant Nos. AFDICT2016-270189, CB-287162, and CF2019-53358.