The role of gene SLC6A20 in cancer and COVID-19

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SLC6A20 is a gene that encodes for a protein called sodium- and chloride-dependent transporter, which is involved in the transport of amino acids and regulates cell growth, proliferation, and differentiation.

Recent studies have suggested a potential association between SLC6A20 and COVID-19 infection, as well as several types of cancer. In this study, we aimed to investigate the expression and potential function of SLC6A20 in COVID-19 and cancer using in silico analysis.

To analyze the role of SLC6A20 in cancer and COVID-19, we conducted a literature review of articles and studies published in peer-reviewed journals. We searched for articles using various databases, including PubMed, Google Scholar, and ScienceDirect, using keywords such as “cancer,” “COVID-19,” “SLC6A20,” and “genetics.” We also looked at the databases of genetic associations and the Cancer Genome Atlas (TCGA) to investigate the association between SLC6A20 and cancer.

Results: Our review of the literature found that SLC6A20 plays a significant role in both cancer and COVID-19. SLC6A20 is an amino acid transporter that is highly expressed in the kidney and is involved in the reabsorption of amino acids.

Studies have shown that SLC6A20 is overexpressed in various types of cancer, including breast, lung, and ovarian cancer, and is associated with poor prognosis.

The gene has also been implicated in COVID-19, with one study reporting that a variant of SLC6A20 was significantly associated with severe COVID-19 infection. The study found that the variant led to a loss of function in the SLC6A20 protein, which is thought to impair the transport of amino acids into cells, leading to a weakened immune response.

We also found that SLC6A20 is located on chromosome 3, which is frequently altered in cancer. Analysis of the TCGA database showed that alterations in SLC6A20 were associated with various types of cancer, including bladder, breast, and lung cancer.

A new study entitled “Pan-Cancer Analysis of the COVID-19 Causal Gene SLC6A20” has highlighted the many connection points between the SLC6A20 gene and the severity of the covid.

Rapid increase in the SARS-CoV-2 infection rates worldwide resulted in an immediate response to understand the underlying mechanisms of the COVID-19 disease, including in cancer patients. Cancer patients are considered as more prone to develop COVID-19 especially because of the impaired immune system response seen in them against the SARS-CoV-2 vaccine. (32,33)

Studies demonstrated that ACE2, TMPRSS2, and TMPRSS4 expression were upregulated and facilitated SARS-CoV-2 infection in tumor samples. (14,34) In addition, certain host-specific genetic factors have been shown to play a critical role in increased susceptibility to COVID-19 in cancer patients. (35)

One of the causal genes identified to be linked with COVID-19 severity was SLC6A20 gene located in the chromosome 3p21.31; (19,20) however, its link with pan-cancer tumor samples remained to be elucidated. Here, we performed systematic analysis of SLC6A20 expression in different malignancies and demonstrated that SLC6A20 was upregulated in a wide number of human pan-cancer samples, and SLC6A20 expression was associated with ACE2, TMPRSS2, and TMPRSS4 genes.

In addition, our findings indicate that there is an interplay between SLC6A20 expression and immune infiltration especially via increased amounts of neutrophils in a number of human tumor samples. Last, SLC6A20 protein interacting with TMEM27, an ACE2 homologue, suggests the potential involvement of SLC6A20 and TMEM27 in COVID-19 in cancer patients.

Two recent studies have characterized the 3p21.31 locus in the severity of COVID-19 disease. (19,20) These studies utilized the genome and epigenome editing approaches to reveal COVID-19 causal genes regulated by the 3p21.31 locus. Among the genes regulated by this locus, SLC6A20, CXCR6, and CCR9 were identified as causal genes to regulate COVID-19 risk in humans.

Since SLC6A20 gene was the only gene independently identified in these two studies for COVID-19 risk, we have focused on SLC6A20 in human tumor samples to investigate SLC6A20 expression in human pan-cancer samples and its association with SARS-CoV-2-related genes and immune infiltration. Our findings indicate that SLC6A20 is highly expressed in a variety of human tumor samples, and there is a positive correlation with SARS-CoV-2 infection genes, ACE2, TMPRSS2, and TMPRSS4, suggesting that SLC6A20 might be involved in modulating COVID-19 disease and hence increased COVID-19 susceptibility for cancer patients.

Subsequently, the relationship between SLC6A20 and immune response in different malignancies was analyzed. The analysis demonstrated that SLC6A20 was highly correlated with neutrophil infiltration in majority of pan-cancer samples including ESCA, KIRP, PAAD, PRAD, BRCA, LIHC, MESO, LUAD, STAD, and UCEC. As elevated immune infiltration is linked with prognosis of human cancers (36,37) and found as an early indicator of COVID-19, (38,39)SLC6A20 might be involved in modulating COVID-19 in cancer patients.

Moreover, the positive association found between SLC6A20 expression and neutrophil infiltration prompted us to think whether SLC6A20 might be involved in regulating the cytokine storm in neutrophils as they are known to be one of the sources of cytokine release in COVID-19 patients. (40,41) However, to support this claim, further functional studies will be needed.

In addition, immune subtypes inflammatory (C3), IFN-λ (C2), wound healing (C1), immunologically quiet (C5), lymphocyte depleted (C4), and TGF-β dominant (C6) analysis revealed an association between SLC6A20, particularly with inflammatory (C3) and IFN-λ (C2) signatures in THYM, READ, COAD, ESCA, and OV samples, suggesting a potential involvement of SCL6A20 in immune modulation in these cancer types.

Given that cancer and COVID-19 share common modalities in terms of being inflammatory (42,43) and the role of IFN-λ (44,45) in both processes, our findings suggest the potential involvement of SCL6A20 in the pathophysiology of COVID-19 in cancer patients. Furthermore, efforts to treat severe COVID-19 patients with hypercytokinemia using emapalumab, an IFN-λ monoclonal antibody, is still underway with a registered clinical trial number of NCT04324021.

SLC6A20 gene encodes the sodium-dependent imino transporter 1 (SIT1) protein. (46) Importantly, it was reported that SIT1 was involved in viral entry and infection of SARS-CoV-2 in the human small intestine via heterodimerization with ACE2. (47) Furthermore, SIT1 was reported to regulate glycine and proline transport. (48)

Moreover, SLC6A20 knockout mice exhibited elevated plasma levels of glycine, suggesting the regulatory role of SLC6A20 in glycine homeostasis. (49) On the contrary, ACE2 knockout mice demonstrated decreased levels of plasma glycine concentration, suggesting the potential use of glycine itself in the treatment of COVID-19 patients. (50) Indeed, it was proposed that glycine could intervene with anti-inflammatory cytokine storm seen in COVID-19 patients via interacting with its receptor GlyR to induce plasma membrane polarization and hence protection against the cytokine storm. (51)

To support this mechanism, one of the drugs used in the treatment of COVID-19 patients was ivermectin, an agonist for glycine-gated chlorine channels. While additional studies are still needed to clarify the antiviral effect of ivermectin in COVID-19 disease, a number of studies demonstrated ivermectin in the treatment of COVID-19. (52,53)

In this study, PPI enrichment analysis showed that TMEM27 was a SLC6A20-associated protein. TMEM27, a homologue of ACE2, (31) has previously been reported as being co-regulated with ACE2 in bronchial samples. (54) Given the prominent role of ACE2 in increased susceptibility in cancer patients and TMEM27 exhibiting 47% homology to ACE2 functions, we speculate that TMEM27 might be involved in the increased susceptibility in cancer patients for COVID-19.

The evaluation of TMEM27 expression in pan-cancer samples resulted in elevated detection of TMEM27 mRNA expression in a number of cancer types such as COAD, GBM, HNSC, KIRC, KIRP, and PRAD. Alongside this observation, TMEM27 expression was found to be correlated predominantly with ACE2 and TMPRSS2 in pan-cancer samples, supporting the link between SLC6A20 binding protein TMEM27 and SARS-CoV-2 infection-related proteins, ACE2 and TMPRSS2 in different cancer types.

reference link : https://pubs.acs.org/doi/10.1021/acsomega.3c00407

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