Extracellular Events Involved in Cancer Cell-Cell Fusion.

Fusion among different cell populations represents a rare process that is mediated by both intrinsic and extracellular events. Cellular hybrid formation is relayed by orchestrating tightly regulated signaling pathways that can involve both normal and neoplastic cells. Certain important cell merger processes are often required during distinct organismal and tissue development, including placenta and skeletal muscle. In a neoplastic environment, however, cancer cell fusion can generate new cancer hybrid cells. Following survival during a subsequent post-hybrid selection process (PHSP), the new cancer hybrid cells express different tumorigenic properties. These can include elevated proliferative capacity, increased metastatic potential, resistance to certain therapeutic compounds, and formation of cancer stem-like cells, all of which characterize significantly enhanced tumor plasticity. However, many parts within this multi-step cascade are still poorly understood. Aside from intrinsic factors, cell fusion is particularly affected by extracellular conditions, including an inflammatory microenvironment, viruses, pH and ionic stress, hypoxia, and exosome signaling. Accordingly, the present review article will primarily highlight the influence of extracellular events that contribute to cell fusion in normal and tumorigenic tissues.

Androgen receptor transactivates KSHV noncoding RNA PAN to promote lytic replication-mediated oncogenesis: A mechanism of sex disparity in KS.

Kaposi's sarcoma-associated herpesvirus (KSHV) preferentially infects and causes Kaposi's sarcoma (KS) in male patients. However, the biological mechanisms are largely unknown. This study was novel in confirming the extensive nuclear distribution of the androgen receptor (AR) and its co-localization with viral oncoprotein of latency-associated nuclear antigen in KS lesions, indicating a transcription way of AR in KS pathogenesis. The endogenous AR was also remarkably higher in KSHV-positive B cells than in KSHV-negative cells and responded to the ligand treatment of 5α-dihydrotestosterone (DHT), the agonist of AR. Then, the anti-AR antibody-based chromatin immunoprecipitation (ChIP)-associated sequencing was used to identify the target viral genes of AR, revealing that the AR bound to multiple regions of lytic genes in the KSHV genome. The highest peak was enriched in the core promoter sequence of polyadenylated nuclear RNA (PAN), and the physical interaction was verified by ChIP-polymerase chain reaction (PCR) and the electrophoretic mobility shift assay (EMSA). Consistently, male steroid treatment significantly transactivated the promoter activity of PAN in luciferase reporter assay, consequently leading to extensive lytic gene expression and KSHV production as determined by real-time quantitative PCR, and the deletion of nuclear localization signals of AR resulted in the loss of nuclear transport and transcriptional activity in the presence of androgen and thus impaired the expression of PAN RNA. Oncogenically, this study identified that the AR was a functional prerequisite for cell invasion, especially under the context of KSHV reactivation, through hijacking the PAN as a critical effector. Taken together, a novel mechanism from male sex steroids to viral noncoding RNA was identified, which might provide a clue to understanding the male propensity in KS.

RNA-dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID-19.

A recent outbreak of coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 has driven a global pandemic with catastrophic consequences. The rapid development of promising therapeutic strategies against COVID-19 is keenly anticipated. Family Coronaviridae comprises positive, single-stranded RNA viruses that use RNA-dependent RNA polymerase (RdRP) for viral replication and transcription. As the RdRP of viruses in this family and others plays a pivotal role in infection, it is a promising therapeutic target for developing antiviral agents against them. A critical genetic driver for many cancers is the catalytic subunit of telomerase: human telomerase reverse transcriptase (hTERT), identified initially as an RNA-dependent DNA polymerase. However, even though hTERT is a DNA polymerase, it has phylogenetic and structural similarities to viral RdRPs. Researchers worldwide, including the authors of this review, are engaged in developing therapeutic strategies targeting hTERT. We have published a series of papers reporting that hTERT has RdRP activity and that this RdRP activity in hTERT is essential for tumor formation. Here, we review the enzymatic function of RdRP in virus proliferation and tumor development, reminding us of how the study of the novel coronavirus has brought us to the unexpected intersection of cancer research and RNA virus research.