Hepatitis C virus (HCV) replication requires annealing of a liver specific microRNA, miR-122 to 2 sites on 5′ untranslated region (UTR). While, microRNAs downregulate gene expression by binding to the 3′ untranslated region of the target mRNA, in this case, the microRNA anneals to the 5′UTR of the viral genomes and upregulates the viral lifecycle. In this review, we explore the current understandings of the mechanisms by which miR-122 promotes the HCV lifecycle, and its contributions to pathogenesis. Annealing of miR-122 has been reported to (a) stimulate virus translation by promoting the formation of translationally active internal ribosome entry site (IRES) RNA structure, (b) stabilize the genome, and (c) induce viral genomic RNA replication. MiR-122 modulates lipid metabolism and suppresses tumor formation, and sequestration by HCV may influence virus pathogenesis. We also discuss the possible use of miR-122 as a biomarker for chronic hepatitis and as a therapeutic target. Finally, we discuss roles for miR-122 and other microRNAs in promoting other viruses.

Hepatitis C virus (HCV) replication requires annealing of a liver specific small-RNA, miR-122 to 2 sites on 5′ untranslated region (UTR). Annealing has been reported to (a) stabilize the genome, (b) stimulate translation and (c) promote the formation of translationally active Internal Ribosome Entry Site (IRES) RNA structure. In this report, we map the RNA element to which small RNA annealing promotes HCV to nucleotides 1–44 and identify the relative impact of small RNA annealing on virus translation promotion and genome stabilization. We mapped the optimal region on the HCV genome to which small RNA annealing promotes virus replication to nucleotides 19–37 and found the efficiency of viral RNA accumulation decreased as annealing moved away from this region. Then, by using a panel of small RNAs that promote replication with varying efficiencies we link the efficiency of lifecycle promotion with translation stimulation. By contrast small RNA annealing stabilized the viral genome even if they did not promote virus replication. Thus, we propose that miR-122 annealing promotes HCV replication by annealing to an RNA element that activates the HCV IRES and stimulates translation, and that miR-122 induced HCV genome stabilization is insufficient alone but enhances virus replication.

Basal cell carcinoma (BCC) is the most common form of skin cancer, contributing to nearly a third of new cancer cases in Western countries. Most BCCs are considered low risk “routine” lesions that can either be excised through surgery or treated with chemotherapeutic agents. However, around 1–2% of BCC cases are locally aggressive, present a high risk of metastasis, and often develop chemoresistance, termed advanced BCC. There currently exists no animal model or cell line that can recapitulate advanced BCC, let alone intermediate-risk and high-risk early BCC. We previously found that aggressive BCC tumours presented a Th2 cytokine inflammation profile, mesenchymal stem cell properties, and macrophage-induced tumoral inflammation. In this study, we aimed to identify potential BCC “relatives” among solid-organ malignancies who present similar immune cell proportions in their microenvironment compositions. Using immune cell type deconvolution by CIBERSORTx, and cell type enrichment by xCell, we determined three cancers with the most similar tumour microenvironments as compared to BCC. Specifically, chromophobe renal cell carcinoma, sarcoma, and skin cutaneous melanoma presented significance in multiple cell types, namely in CD4+ T lymphocytes, gammadelta T lymphocytes, and NK cell populations. Consequently, further literature analysis was conducted to understand similarities between BCC and its “relatives”, as well as investigating novel treatment targets. By identifying cancers most like BCC, we hope to propose prospective druggable pathways, as well as to gain insight on developing a reliable animal or cell line model to represent advanced BCC.

29Hepatitis C virus (HCV) genome replication requires annealing of a liver specific small-30 RNA, miR-122 to 2 sites on 5' untranslated region (UTR). Annealing has been reported to a) 31 stabilize the genome, b) promote translation, and c) induce the canonical HCV 5' UTR Internal 32Ribosome Entry Site (IRES) structure. In this report we identify the relative impact of small RNA 33 annealing on the three functions ascribed to miR-122 and generate a mechanistic model for miR-34 122 promotion of HCV. First, we identified that perfectly complementary small RNAs that anneal 35 to different locations on the HCV 5' UTR stimulate replication with varying efficiencies and 36 mapped the region on the HCV genome to which small RNA annealing promotes virus replication. 37Second, by using a panel of small RNAs that promote with varying efficiencies we link HCV 38 replication induction with translation stimulation and 5' UTR RNA structure modifications. 39However, replication promotion was not linked to genome stabilization since all small RNAs 40 tested could stabilize the viral genome regardless of their ability to promote replication. Thus, we 41propose that miR-122 annealing promotes HCV replication primarily by activating the HCV IRES 42 and stimulating translation, and that miR-122-induced HCV genome stabilization is insufficient 43 alone but enhances virus replication. 44 45 46 47