Exosomal Cargo as potential Biomarker in HCV mediated Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is now regarded as one of the most common and prevailing type of cancer globally, as it constitutes more than 7% of all cancers. Mainly 80% of HCC occurrence is viral borne, and HBV/HCV are the main major culprits behind it. Hepatic cellular carcinoma due to HCV infection is among the major risk factors which leads to increased metastasis and progression of liver cancer. HCV infection is a prominent and major risk factor which leads to increased metastasis and chronic liver infection in HCC. In this regard, it is estimated that around 200 million individuals globally are the carriers of HCV and have greater chance of HCV-mediate HCC.Pakistan has witnessed increased burden of hepatocellular carcinoma in recent years, it is among those countries which are struggling to tackle this serious health issue in order to improve diagnosis, prognosis and treatment. For the histological grading of HCC, tissue biopsy has been regarded as gold standard. There are many limitations which are associated with tissue biopsy such as non-feasibility due to tumor heterogeneity, periodic monitoring for progression recurrence, costly and above of all invasive painful procedures. Since the last decade, liquid biopsy has become an appealing alternative to overcome above major challenges by offering minimally invasive to noninvasive personalized procedures. Since the last decade, exosomes based biomarker discovery for diagnosis and prognosis of cancer has gained the attention of scientific community. Exosomes are small extracellular vesicles which were firstly considered as waste disposal system but now they are emerging as powerful signal mediators. Almost any cell type in our body can secret these vesicles and they can be retrieved successfully from body fluid such as blood, saliva, urine and amniotic fluid. In HCV-mediated HCC, exosomes are majorly involved in the communication between HCC cells and play important role in metastasis, immune evasion and invasion of HCC.Biochemical content of exosomes include lipids, proteins, soluble growth mediators and nucleic acids mainly miRNAs and mRNA .In addition, HCC derived exosomes-mediated microRNAs transfer is significant in the modulation of microenvironment for hepatocyte growth and progression. Exosomal miRNAs can be used in the detection and monitoring of HCC cells. They show tremendous potential to serve as diagnostic biomarkers for early stage tumors and metastasis of HCC cells. The objective of our study was identification of potential exosomal miRNAs biomarkers via insilico tools. The results showed us that exosomes are important in development of persistent Hepatitis C (HCV) infection. This involves the association of HCV particles with exosomes. There are two proposed hypothesis for this association: 1.HCV virion via exosomes as cargo, 2. HCV virion via exosomes on surface. The exosomal transfer and immune evasion of HCV has been confirmed in cell culture. Here we provide evidence of both forms of HCV virion exosomal association, with exosomes on surface and as exosomal cargo, in sera from HCV infected Hepatocellular Carcinoma (HCC). We have also predicted potential miRNAs biomarkers that are present in exosomes via Meta-analysis. In silico analysis shows that miR-18a-5p, miR-21, miR-224-3p, miR-224-5p, miR- 199a-3p and miR-199a-5p in exosomes may be potential best predictive markers in HCV mediated HCC for clinical diagnostics and prognostics. Further in vitro validation of predicted biomarkers is yet to be established.