The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance, which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene, which is involved in the regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow the completion of their viral replication cycles. Furthermore, a dataset using a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs, which negatively correlated with the expression of genes that code for sterol response element-binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Moreover, ACE2 expression in human subcutaneous adipose tissue can be regulated through changes in diet. Validation of the in silico data revealed a higher expression of ACE2, TMPRSS2 and SREBP1 in vitro in lung epithelial cells from obese subjects compared to non-obese subjects. To our knowledge this is the first study to show upregulation of ACE2 and TMPRSS2 in obesity. In silico and in vitro results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.
Current guidelines for COVID-19 management recommend the utilization of various repurposed drugs. Despite ongoing research toward the development of a vaccine against SARS-CoV-2, such a vaccine will not be available in time to contribute to the containment of the ongoing pandemic. Therefore, there is an urgent need to develop a framework for the rapid identification of novel targets for diagnostic and therapeutic interventions. We analyzed publicly available transcriptomic datasets of SARS-CoV infected humans and mammals to identify consistent differentially expressed genes then validated in SARS-CoV-2 infected epithelial cells transcriptomic datasets. Comprehensive toxicogenomic analysis of the identified genes to identify possible interactions with clinically proven drugs was carried out. We identified IFITM3 as an early upregulated gene, and valproic acid was found to enhance its mRNA expression as well as induce its antiviral action. These findings indicate that analysis of publicly available transcriptomic and toxicogenomic data represents a rapid approach for the identification of novel targets and molecules that can modify the action of such targets during the early phases of emerging infections like COVID-19.
Prolactin (PRL) hormone plays an important role in the development of the mammary gland and terminal differentiation of the mammary epithelial cells. While initial studies suggested that PRL may contribute to the development of breast cancer through PRL/prolactin receptor (PRLR) autocrine function, mounting evidence indicate a different role for PRL, highlighting this hormone as a regulator of epithelial plasticity and as a potential tumor suppressor. To gain further insights into the role of PRL in human breast carcinogenesis, immunohistochemistry analyses of PRLR protein expression levels using tissue microarray of 102 cases were done in comparison with various clinical/pathologic parameters and molecular subtypes. In addition, gene expression level of PRLR was also evaluated in relation to intrinsic molecular subtypes, tumor grade, and patient outcome using GOBO database for 1881 breast cancer patients. Interestingly, PRLR expression was found to be significantly downregulated in invasive breast cancer (21.4%) in comparison with normal/benign (80%) and in situ carcinoma (60%) (P=0.003498). Moreover, PRLR expression was associated with lymph node negativity and low-grade well-differentiated tumors. PRLR expression was strongest in luminal A subtype, and was virtually undetectable in the worse prognosis triple-negative breast cancer subtype (P=0.00001). Furthermore, PRLR expression was independent of ER, PR, HER-2, and P53 status. Finally, PRLR expression was significantly (P<0.01) associated with prolonged distant metastasis-free survival in breast cancer patients. In conclusion, our results highlight PRLR as an independent predictor of favorable prognosis in human breast cancer.
Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, display poor prognosis and exhibit resistance to conventional therapies, partly due to an enrichment in breast cancer stem cells (BCSCs). Here, we investigated the role of the cyclooxygenase-2 (COX-2), a downstream target of TGFβ, in regulating BCSCs in TNBC. Bioinformatics analysis revealed that COX-2 is highly expressed in TNBC and that its expression correlated with poor survival outcome in basal subtype of breast cancer. We also found TGFβ-mediated COX-2 expression to be Smad3-dependent and to be required for BCSC self-renewal and expansion in TNBCs. Knocking down COX-2 expression strikingly blocked TGFβ-induced tumorsphere formation and TGFβ-induced enrichment of the two stem-like cell populations, CD24lowCD44high and ALDH+ BCSCs. Blocking COX-2 activity, using a pharmacological inhibitor also prevented TGFβ-induced BCSC self-renewal. Moreover, we found COX-2 to be required for TGFβ-induced expression of mesenchymal and basal breast cancer markers. In particular, we found that TGFβ-induced expression of fibronectin plays a central role in TGFβ-mediated breast cancer stemness. Together, our results describe a novel role for COX-2 in mediating the TGFβ effects on BCSC properties and imply that targeting the COX-2 pathway may prove useful for the treatment of TNBC by eliminating BCSCs.
The ongoing COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. Age, smoking, obesity, and chronic diseases such as cardiovascular disease and diabetes have been described as risk factors for severe complications and mortality in COVID-19. Obesity and diabetes are usually associated with dysregulated lipid synthesis and clearance which can initiate or aggravate pulmonary inflammation and injury. It has been shown that for viral entry into the host cell, SARS-CoV-2 utilizes the angiotensin converting enzyme 2 (ACE2) receptors present on the cells. We aimed to characterize how SARS-CoV-2 dysregulates lipid metabolism pathways in the host and the effect of dysregulated lipogenesis on the regulation of ACE2, specifically in obesity. In our study, through the re-analysis of publicly available transcriptomic data, we first found that lung epithelial cells infected with SARS-CoV-2 showed upregulation of genes associated with lipid metabolism, including the SOC3 gene which is involved in regulation of inflammation and inhibition of leptin signaling. This is of interest as viruses may hijack host lipid metabolism to allow completion of their viral replication cycles. Furthermore, a mouse model of diet-induced obesity showed a significant increase in Ace2 expression in the lungs which negatively correlated with the expression of genes that code for sterol response element binding proteins 1 and 2 (SREBP). Suppression of Srebp1 showed a significant increase in Ace2 expression in the lung. Together our results suggest that the dysregulated lipogenesis and the subsequently high ACE2 expression in obese patients might be the mechanism underlying the increased risk for severe complications in those patients when infected by SARS-CoV-2.
Triple negative breast cancer (TNBC) is a heterogeneous disease associated with poor clinical outcome and lack of targeted therapy. Here we show that prolactin (PRL) and its signaling pathway serve as a sub-classifier and predictor of pro-differentiation therapy in TNBC. Using immunohistochemistry and various gene expression in silica analyses we observed that prolactin receptor (PRLR) protein and mRNA levels are down regulated in TNBC cases. In addition, examining correlation of PRLR gene expression with metagenes of TNBC subtypes (580 cases), we found that PRLR gene expression sub-classifies TNBC patients into a new subgroup (TNBC-PRLR) characterized by epithelial-luminal differentiation. Importantly, gene expression of PRL signaling pathway components individually (PRL, PRLR, Jak2 and Stat5a), or as a gene signature is able to predict TNBC patients with significantly better survival outcomes. As PRL hormone is a druggable target we determined the biological role of PRL in TNBC biology. Significantly, restoration/activation of PRL pathway in TNBC cells representative of mesenchymal or TNBC-PRLR subgroups led to induction of epithelial phenotype and suppression of tumorigenesis. Altogether, these results offer potential new modalities for TNBC stratification and development of personalized therapy based on PRL pathway activation.
Breast cancer consists of a range of tumor subtypes with different clinical characteristics, disease prognosis, and treatment-response. Luminal breast cancer has the best prognosis while basal-like breast cancer (BLBC) represents the worst subtype. Transforming growth factor-beta (TGFβ) plays a prominent role in stimulating the migration and invasion of malignant breast cancer cells contributing to tumor progression. In this study, we identified the Ephrin type-A receptor 4 (EPHA4) as a novel target of TGFβ in breast cancer. Moreover, we show that TGFβ induction of EPHA4 gene expression is specific to basal-like tumors and is required for TGFβ-mediated cell migration. We further addressed the mechanism and found EPHA4 to be required for TGFβ-mediated cell migration in breast cancer through TGFβ-induced short term and long term activation of RhoGTPases. Finally, our data revealed a strong association between high EPHA4 expression and advanced tumor stage, aggressive BLBC molecular subtype and poor prognosis. Importantly, we found significant co-expression of EPHA4 and the TGFβ receptor type-2 (TGFβR2) in breast cancer subtypes associated with increased tumor relapse and drug resistance. Together, this study highlight the important role of the TGFβ/EPHA4 signaling axis in mediating tumor aggressiveness and poor patient survival in human breast cancer.
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