Approaches for Detection of Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins and Their Application in Prediction of Higher Risk of Hepatocellular Carcinoma Development and Recurrence.

Yueh-Te Lin,Ih-Jen Su,Long-Bin Jeng,Chiao-Fang Teng

doi:10.3390/v14020428

Abstract

Hepatocellular carcinoma (HCC) is among the most common and lethal human cancers worldwide and is closely associated with chronic hepatitis B virus (HBV) infection. Pre-S deleted proteins are naturally occurring mutant forms of HBV large surface proteins that are expressed by HBV surface genes harboring deletion mutations over the pre-S gene segments. It has been well demonstrated that HBV pre-S deleted proteins function as important oncoproteins, which promote malignant phenotypes of hepatocytes through the activation of multiple oncogenic signaling pathways and result in HCC formation. The oncogenic signaling pathways activated by pre-S deleted proteins have been verified as potential therapeutic targets for the prevention of HCC development. Moreover, the presence of pre-S gene deletions and the expression of pre-S deleted proteins in the blood and liver tissues of HBV-infected patients have been evaluated as valuable biomarkers for predicting a higher risk of HCC development and recurrence after curative surgical resection. Therefore, the precise detection of pre-S gene deletions and pre-S deleted proteins holds great promise as regards identifying the patients at higher risk of HCC development and recurrence, thus aiding in more timely and better treatments to improve their survival. This review summarizes the major approaches used for the detection of pre-S gene deletions and pre-S deleted proteins, including the approaches based on Sanger DNA sequencing, pre-S gene chips, next-generation sequencing and immunohistochemistry staining, and it highlights their important applications in the prediction of higher risks of HCC development and recurrence.

Highlights

Curative surgical resection is available for hepatocellular carcinoma (HCC) patients, the recurrence rate of HCC within five years after surgery is as high as 70%, leading to poor patient outcomes [5,6]
The IHC staining-based approach is the only one of these approaches to detect the expression pattern of pre-S deleted proteins in the liver tissues; because the liver tissue sections used for IHC staining were partial liver tissues, the results obtained by this approach may insufficiently represent the whole liver tissue [37]
Because the increased infiltration and activation of Tregs and the increased expression of programmed death ligand 1 (PD-L1) in HCC tissues have been associated with poor prognoses [23,24,40], our results suggest that inhibitors targeting Tregs and PD-L1 are promising therapeutics for treating HCC patients infected with hepatitis B virus (HBV) with pre-S gene deletions

Summary

Introduction

As a predominant form of primary liver cancer, hepatocellular carcinoma (HCC). Accounts for nearly 90% of all liver malignancies [1,2]. Despite significant advances made in detection, prevention, and therapy, HCC is still the six most frequently diagnosed human cancer and the third leading cause of cancer-related death worldwide, leading to approximately 800,000 deaths annually [3,4]. Curative surgical resection is available for HCC patients, the recurrence rate of HCC within five years after surgery is as high as 70%, leading to poor patient outcomes [5,6]. The development of valuable biomarkers, along with approaches for the precise detection of the biomarkers, is still a key goal for the early identification and timely treatment of patients at higher risk of HCC development and recurrence, helping to improve their survival

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