From viruses to cancer: exploring the role of the hepatitis C virus NS3 protein in carcinogenesis

Abstract

Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide and is a known etiological agent of hepatocellular carcinoma (HCC). The molecular mechanisms of HCV-mediated carcinogenesis are not fully understood. This review article focuses on the oncogenic potential of NS3, a viral protein with transformative effects on cells, although the precise mechanisms remain elusive. Unlike the more extensively studied Core and NS5A proteins, NS3's roles in cancer development are less defined but critical. Research indicates that NS3 is implicated in several carcinogenic processes such as proliferative signaling, cell death resistance, genomic instability and mutations, invasion and metastasis, tumor-related inflammation, immune evasion, and replicative immortality. Understanding the direct impact of viral proteins such as NS3 on cellular transformation is crucial for elucidating HCV's role in HCC development. Overall, this review sheds light on the molecular mechanisms used by NS3 to contribute to hepatocarcinogenesis, and highlights its significance in the context of HCV-associated HCC, underscoring the need for further investigation into its specific molecular and cellular actions.

Fig. 1

Representation of HCV-NS3 domains. (A) N-terminal contains the protease domain from residues 1–180 represented in purple. Residues His⁵⁷, Asp⁸¹ and Ser¹³⁹ compose the catalytic triad. C-terminal contains a NTPase/helicase domain from 180 to 631, itself composed of three domains represented in different shades of blue. Helicase domain I, Ia and III to VI are shown in domains 1 and 2. (B) 3D representation of NS3 from genotype 1b obtained by X-ray diffraction (PDB: 3O8B). The same color code was used as in (A), residues in the catalytic triad are in orange and represented in their gaussian surface form

Fig. 2

Visual summary of the different mechanisms by which NS3 could contribute to carcinogenesis

Fig. 3

Percent identity matrix of NS3 alignment from different Flaviviridae. Alignment and analysis were done with Uniprot Align tool with the Clustal Omega program. HCV genotype 1b isolate BK (P26663); WNV strain NY99 (Q9Q6P4); KUNJIN strain MRM61C (P14335); ZIKA strain MR 766 (Q32ZE1); DENV type 2 strain IQT2913 (Q9WDA6); HPgV-1 (Q69422)