Targeting AFP-RARß complex formation: a potential strategy for treating AFP-positive hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a glycoprotein primarily expressed during embryogenesis, with declining levels postnatally. Elevated AFP levels correlate with pathological conditions such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Recent investigations underscore AFP's intracellular role in HCC progression, wherein it forms complexes with proteins like Phosphatase and tensin homolog (PTEN), Caspase 3 (CASP3), and Retinoic acid receptors and Retinoid X receptors (RAR/RXR). RAR and RXR regulate gene expression linked to cell death and tumorigenesis in normal physiology. AFP impedes RAR/RXR dimerization, nuclear translocation, and function, promoting gene expression favoring cancer progression in HCC that provoked us to target AFP as a drug candidate. Despite extensive studies, inhibitors targeting AFP to disrupt complex formation and activities remain scarce. In this study, employing protein-protein docking, amino acid residues involved in AFP-RARß interaction were identified, guiding the definition of AFP's active site for potential inhibitor screening. Currently, kinase inhibitors play a significant role in cancer treatment and, the present study explores the potential of repurposing FDA-approved protein kinase inhibitors to target AFP. Molecular docking with kinase inhibitors revealed Lapatinib as a candidate drug of the AFP-RARß complex. Molecular dynamics simulations and binding energy calculations, employing Mechanic/Poisson-Boltzmann Surface Area (MM-PBSA), confirmed Lapatinib's stability with AFP. The study suggests Lapatinib's potential in disrupting the AFP-RARß complex, providing a promising avenue for treating molecularly stratified AFP-positive HCC or its early stages.

Etiologically Significant microRNAs in Hepatitis B Virus-Induced Hepatocellular Carcinoma.

Hepatitis B virus (HBV) infection has been causally linked to hepatocellular carcinoma (HCC) in more than 50% cases. MicroRNAs (miRNAs) play cross-cutting mechanistic roles in the complex interplay between viral pathogenesis, host survival, and clinical outcomes. The present study set out to identify etiologically significant human miRNAs associated with HBV infection in liver-related pathologies leading to HCC. In diverse tissue types, we assembled 573 miRNAs differentially expressed in HBV-associated liver pathologies, HBV infection, fibrosis, cirrhosis, acute on chronic liver failure, and HCC. Importantly, 43 human differentially expressed miRNAs (hDEmiRs) were regulated in serum/plasma and liver tissue of patients with HBV-positive conditions. However, only two hDEmiRs, hsa-miR-21-5p and hsa-miR-143-3p, were regulated across all disease conditions. To shortlist the functional miRNAs in HBV-induced HCC pathogenesis, a reverse bioinformatics analysis was performed using eight GEO datasets and the TCGA database containing the list of differentially regulated mRNAs in HCC. A comparative study using these data with the identified targets of hDEmiRs, a set of unidirectionally regulated hDEmiRs with the potential to modulate mRNAs in HCC, were found. Moreover, our study identified five miRNAs; hsa-miR-98-5p, hsa-miR-193b-3p, hsa-miR-142-5p, hsa-miR-522-5p, and hsa-miR-370-3p targeting PIGC, KNTC1, CSTF2, SLC41A2, and RAB17, respectively, in HCC. These hDEmiRs and their targets could be pivotal in HBV infection and subsequent liver pathologies modulating HCC clinical progression. HBV infection is the largest contributor to HCC, and the present study comprises the first of its kind compendium of hDEmiRs related to HBV-related pathologies.

Riddling Substitution of "hsa" to "has" in the Enigmatic MicroRNA Nomenclature.

This concise review and analysis offers an initial unpacking of a previously under-recognized issue within the microRNA research and communications field regarding the inadvertent use of "has" instead of "hsa" in article titles in the microRNA nomenclature. This subtle change, often the result of grammar auto correction tools, introduces considerable ambiguity and confusion among readers and researchers in reporting of microRNA-related discoveries. The impact of this issue cannot be underestimated, as precise and consistent nomenclature is vital for science communication and computational retrieval of relevant scientific literature and to advance science and innovation. We suggest that the recognition and correction of these often inadvertent "hsa" to "has" substitution errors are timely and important so as to ensure a higher level of accuracy throughout the writing and publication process in the microRNA field in particular. Doing so will also contribute to clarity and consistency in the field of microRNA research, ultimately improving scientific veracity, communication, and progress.

Hepatitis B Virus Modulated Transcriptional Regulatory Map of Hepatic Cellular MicroRNAs.

Hepatitis B virus (HBV) is an enveloped, hepatotropic, noncytopathic virus with a partially double-stranded DNA genome. It infects hepatocytes and is associated with progression to liver fibrosis and cirrhosis, culminating in hepatocellular carcinoma (HCC), accounting for 55% of total HCC cases. MicroRNAs (miRNAs) regulated by HBV play an important role in these pathologies. Mapping the miRNAs responsive to HBV and HBV-specific proteins, including HBV X protein (HBx) that harbor the majority of HBV-human protein interactions, could aid accelerate the diagnostics and therapeutics innovation against the infection and associated diseases. With this in mind, we used a unique annotation strategy whereby we first amassed 362 mature HBV responsive-human Differentially Expressed miRNAs (HBV-hDEmiRs). The core experimentally-validated messenger RNA targets of the HBV-hDEmiRs were mostly associated with viral infections and hepatic inflammation processes. Moreover, our annotation strategy enabled the characterization of HBx-dependent/independent HBV-hDEmiRs as a tool for evaluation of the impact of HBx as a therapeutic target. Bioinformatics analysis of the HBV-human protein-protein interactome revealed new insights into the transcriptional regulatory network of the HBV-hDEmiRs. We performed a comparative analysis of data on miRNAs gathered from HBV infected cell line studies and from tissue studies of fibrosis, cirrhosis, and HCC. Accordingly, we propose hsa-miR-15a-5p that is downregulated by multiple HBV proteins, including HBx, as a potential biomarker of HBV infection, and its progression to HCC. In all, this study underscores (1) the complexity of miRNA regulation in response to HBV infection and its progression into other liver pathologies and (2) provides a regulatory map of HBV-hDEmiRs and the underlying mechanisms modulating their expression through a cross talk between HBV viral proteins and human transcription factors.