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An investigation into the molecular basis of cancer comorbidities in coronavirus infection.

ABSTRACT: Comorbidities in COVID-19 patients often worsen clinical conditions and may represent death predictors. Here, the expression of five genes, known to encode coronavirus receptors/interactors (ACE2, TMPRSS2, CLEC4M, DPP4 and TMPRSS11D), was investigated in normal and cancer tissues, and their molecular relationships with clinical comorbidities were investigated. Using expression data from GENT2 databases, we evaluated gene expression in all anatomical districts from 32 normal tissues in 3902 individuals. Functional relationships with body districts were analyzed by chilibot. We performed DisGeNet, genemania and DAVID analyses to identify human diseases associated with these genes. Transcriptomic expression levels were then analyzed in 31 cancer types and healthy controls from approximately 43 000 individuals, using GEPIA2 and GENT2 databases. By performing receiver operating characteristic analysis, the area under the curve (AUC) was used to discriminate healthy from cancer patients. Coronavirus receptors were found to be expressed in several body districts. Moreover, the five genes were found to associate with acute respiratory syndrome, diabetes, cardiovascular diseases and cancer (i.e. the most frequent COVID-19 comorbidities). Their expression levels were found to be significantly altered in cancer types, including colon, kidney, liver, testis, thyroid and skin cancers (P < 0.0001); AUC > 0.80 suggests that TMPRSS2, CLEC4M and DPP4 are relevant markers of kidney, liver, and thyroid cancer, respectively. The five coronavirus receptors are related to all main COVID-19 comorbidities and three show significantly different expression in cancer versus control tissues. Further investigation into their role may help in monitoring other comorbidities, as well as for follow-up of patients who have recovered from SARS-CoV-2 infection.

SUBMITTER: Facchiano A

PROVIDER: S-EPMC7537529 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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An investigation into the molecular basis of cancer comorbidities in coronavirus infection.

Facchiano Antonio A Facchiano Francesco F Facchiano Angelo A

FEBS open bio 20201012 11

Comorbidities in COVID-19 patients often worsen clinical conditions and may represent death predictors. Here, the expression of five genes, known to encode coronavirus receptors/interactors (ACE2, TMPRSS2, CLEC4M, DPP4 and TMPRSS11D), was investigated in normal and cancer tissues, and their molecular relationships with clinical comorbidities were investigated. Using expression data from GENT2 databases, we evaluated gene expression in all anatomical districts from 32 normal tissues in 3902 indiv ...[more]

PMID: 32970391

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Project description:OBJECTIVE:?-Aminobutyric acid type A (GABAA ) receptor subunit gene mutations are significant causes of epilepsy, which are often accompanied by various neuropsychiatric comorbidities, but the underlying mechanisms are unclear. It has been suggested that the comorbidities are caused by seizures, as the comorbidities often present in severe epilepsy syndromes. However, findings from both humans and animal models argue against this conclusion. Mutations in the GABAA receptor ?2 subunit gene GABRG2 have been associated with anxiety alone or with severe epilepsy syndromes and comorbid anxiety, suggesting that a core molecular defect gives rise to the phenotypic spectrum. Here, we determined the pathophysiology of comorbid anxiety in GABRG2 loss-of-function epilepsy syndromes, identified the central nucleus of the amygdala (CeA) as a primary site for epilepsy comorbid anxiety, and demonstrated a potential rescue of comorbid anxiety via neuromodulation of CeA neurons. METHODS:We used brain slice recordings, subcellular fractionation with Western blot, immunohistochemistry, confocal microscopy, and a battery of behavior tests in combination with a chemogenetic approach to characterize anxiety and its underlying mechanisms in a Gabrg2+/Q390X knockin mouse and a Gabrg2+/- knockout mouse, each associated with a different epilepsy syndrome. RESULTS:We found that impaired GABAergic neurotransmission in CeA underlies anxiety in epilepsy, which is due to reduced GABAA receptor subunit expression resulting from the mutations. Impaired GABAA receptor expression reduced GABAergic neurotransmission in CeA, but not in basolateral amygdala. Activation or inactivation of inhibitory neurons using a chemogenetic approach in CeA alone modulated anxietylike behaviors. Similarly, pharmacological enhancement of GABAergic signaling via ?2 subunit-containing receptors relieved the anxiety. SIGNIFICANCE:Together, these data demonstrate the molecular basis for a comorbidity of epilepsy, anxiety, and suggest that impaired GABAA receptor function in CeA due to a loss-of-function mutation could at least contribute to anxiety. Modulation of CeA neurons could cause or suppress anxiety, suggesting a potential use of CeA neurons as therapeutic targets for treatment of anxiety in addition to traditional pharmacological approaches.

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An investigation into the molecular basis of cancer comorbidities in coronavirus infection.

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An investigation into the molecular basis of cancer comorbidities in coronavirus infection.

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