The nuclear transport machinery in hepatocellular carcinoma: From precancerous lesions to progression and therapeutic targeting

Nucleocytoplasmic transport, a vital cellular process through which molecules such as RNA and proteins are shuttled between the nucleus and the cytoplasm, is facilitated by the nuclear transport machinery (NTM). The NTM consists of karyopherins (including importins and exportins), nucleoporins, and the Ran system, all of which possess specific functions. NTM dysregulation is commonly observed during tumorigenesis, leading to the intracellular mislocalization of oncoproteins and tumor suppressors and thereby facilitating cancer progression. The significance of NTM dysfunction in hepatocellular carcinoma (HCC) has gained increased recognition in recent years. Such abnormalities are observed in precancerous liver conditions and HCC, affecting intracellular trafficking and potentially inducing irregular gene expression and cellular aberrations. Given the limited efficacy of current treatments for advanced HCC and the prevalent issue of drug resistance, understanding these early abnormalities of liver cancer progression is crucial for blocking disease progression from hepatitis and liver fibrosis to cirrhosis and HCC. Among therapeutic strategies, targeted inhibition of XPO1-mediated nuclear export has emerged as a promising intervention for various cancers. Selective inhibitors of nuclear export (SINEs) have recently advanced into clinical trials for various malignancies and have been combined with other drugs to enhance efficacy and overcome resistance. However, the roles of inhibitors targeting other importin and exportin family members require further mechanistic and clinical exploration. This paper provides an overview of the molecular mechanisms underlying the role of the NTM in HCC progression and discusses the therapeutic prospects of targeting nucleocytoplasmic transport.