An analysis of SARS-CoV-2 cell entry genes identifies the intestine and colorectal cancer as susceptible tissues.

SARS-CoV-2 is the causative agent for the COVID-19 pandemic. COVID-19 has necessitated rapid changes in surgical practice and organisation through both the initial peak and ongoing recovery period 1. SARS-CoV-2 infects cells by interacting with the host cell surface protein ACE2 and utilises TMPRSS2 in viral spike protein priming to facilitate cell entry (Fig. 1a) 2. Whilst COVID-19 is predominantly a respiratory disease approximately 15% of patients have concurrent gastrointestinal symptoms 3. SARS-CoV-2 RNA and live virus have been identified in stool from COVID-19 patients and SARS-CoV-2 readily infects intestinal organoids 4-6. Despite these circumstantial data, gastrointestinal transmission has not yet been formally confirmed. Cancers commonly express different genes from the tissue of origin and it is largely unexplored whether tumours can be infected with SARS-CoV-2. We sought to explore the expression of ACE2 and TMPRSS2 in large publicly available normal tissue and pan-cancer expression data sets to understand whether levels of these genes identify susceptible tissues.SJAB is supported by an Advanced Clinician Scientist Fellowship grant from Cancer Research UK C14094/A27178; and core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute

ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium.

The telomeric amplicon at 8p12 is common in oestrogen receptor-positive (ER+) breast cancers. Array-CGH and expression analyses of 1172 primary breast tumours revealed that ZNF703 was the single gene within the minimal amplicon and was amplified predominantly in the Luminal B subtype. Amplification was shown to correlate with increased gene and protein expression and was associated with a distinct expression signature and poor clinical outcome. ZNF703 transformed NIH 3T3 fibroblasts, behaving as a classical oncogene, and regulated proliferation in human luminal breast cancer cell lines and immortalized human mammary epithelial cells. Manipulation of ZNF703 expression in the luminal MCF7 cell line modified the effects of TGFβ on proliferation. Overexpression of ZNF703 in normal human breast epithelial cells enhanced the frequency of in vitro colony-forming cells from luminal progenitors. Taken together, these data strongly point to ZNF703 as a novel oncogene in Luminal B breast cancer

Potential pathophysiological role of microRNA 193b-5p in human placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are pregnancy complications resulting from abnormal placental development. MicroRNAs can regulate placental development and contribute to disease, by influencing gene expression. Our previous study revealed an increase in miR-193b-5p expression in placentae from patients with early-onset pregnancy complications and identified candidate gene targets for miR-193b-5p. The purpose of this study is two-fold, first to validate candidate gene targets predicted for miR-193b-5p from microRNA-RNA expression data. Second, to overexpress miR-193b-5p in a trophoblast cell line (HTR-8/SVneo) to assess impact on trophoblast cell proliferation and migration. Integration of the miRNA and RNA sequencing expression data revealed 10 candidate gene targets for miR-193b-5p across all patient groups (PE only, IUGR only, PE + IUGR). Luciferase experiments identified two gene targets for miR-193b-5p, APLN and FGF13. Real-time PCR confirmed a median 45% decrease of FGF13 expression across 3 patient groups, and 50% decrease of APLN expression in patients with PE + IUGR. Following transfection of HTR-8/SVneo cells with miR-193b-5p mimics, APLN and FGF13 mRNA expression in HTR-8/SVneo was reduced by a median percentage of 30% and 45%, respectively. Concomitantly, HTR-8/SVneo cells demonstrate 40% reduction in cell migration. APLN and FGF13 immunoreactivity was identified strongly in the cytotrophoblast cells of the human placentae. These findings suggest that miR-193b-5p may contribute to trophoblast dysfunction observed in pregnancy complications such as PE and IUGR