Analyzing the Potential of Platelets RNA as Biomarker Trove for Diagnostic Comparison of Hepatic Cirrhosis and Hepatocellular Carcinoma

Abstract

Hepatic cirrhosis and Hepatocellular carcinoma (HCC) significantly contribute to the global disease burden and mortality rates. According to the global estimates, cirrhosis is 11th leading cause of deaths in adults while Hepatocellular carcinoma is the second deadliest cancer, cirrhosis being the leading cause of its occurrence. With the advancement of novel approaches to cater to the surging liver diseases, efforts in the quest for ideal liquid biopsy biomarker have also increased. Among the multiplicity of factors involved in rising incidence of HCC, its late diagnosis and difficulty in differentiation between late stage cirrhosis from early stage HCC are the major ones. Moreover, the invasiveness of tissue biopsy and the associated risks involved, costly diagnostic tests and the time intensive procedures are the major drawbacks of currently employed diagnostic methods. This necessitates the amelioration of diagnostic tests for earlier diagnosis of HCC and the ability to predict its progression from underlying cirrhosis. In recent years, Platelets have emerged as a strong multimodal tool to be used in liquid biopsies of cancers due to their ability to interact with tumor cells leading to change in their RNA content leading to their ‘tumor education’. This characteristic of tumoreducated platelets (TEPs) makes them a strong candidate for the current study designed for identification of biomarkers for diagnostic comparison of late-stage cirrhosis and earlystage HCC. In the present study, selected mRNA repertoire of platelets was used as a liquid biopsybased biomarker for assessing their differential expression in HCC patients as compared to both; cirrhosis patients and controls. Among the tested biomarkers, RhoA, CTNNB1 and SPINK1 showed promising potential to be utilized as a biomarker for comparison of cirrhosis and HCC with a significant 3.3-, 3.2- and 3.18-fold change, respectively. IFITM3 and SERPIND1 also gave a significant 2.24-fold change, each, in HCC patients as compared to cirrhosis group. One of the selected genes, TERT, showed markedly low expression in HCC patients while in cirrhosis and controls, this transcript was undetectable at the 1μg concentration used. This could be potentially an iconic candidate for differential expression profiling of cirrhosis and HCC patients. Moreover, these biomarkers also showed great potential to be used for screening and earlier detection of HCC when compared to controls. IFITM3, CTNNB1 and RhoA showed a significant 7.5-, 4.47- and 3.43-fold increase in HCC patients in comparison to controls, respectively. SPINK1 also depicted a 1.7-fold increase in case of HCC. Taken together, the significant change in platelet mRNA for aforementioned biomarkers suggests that they exhibit promising potential for use in the liquid biopsy for diagnostic comparison of late-stage cirrhosis and early-stage HCC. Given the findings, this study can potentially lead to the development of noninvasive liquid biopsy test and real time monitoring of the disease status of cirrhotic and HCC patients.