Expression Of Transmembrane Protease Serine 2 Research Articles

Pan‑cancer analysis of transmembrane protease serine 2 and cathepsin L that mediate cellular SARS‑CoV‑2 infection leading to COVID-19.

Severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV2) is the cause of a new disease (COVID-19) which has evolved into a pandemic during the first half of 2020. Older age, male sex and certain underlying diseases, including cancer, appear to significantly increase the risk for severe COVID-19. SARS-CoV-2 infection of host cells is facilitated by the angiotensin-converting enzyme 2 (ACE-2), and by transmembrane protease serine 2 (TMPRSS2) and other host cell proteases such as cathepsin L (CTSL). With the exception of ACE-2, a systematic analysis of these two other SARS-CoV2 infection mediators in malignancies is lacking. Here, we analysed genetic alteration, RNA expression, and DNA methylation of TMPRSS2 and CTSL across a wide spectrum of tumors and controls. TMPRSS2 was overexpressed in cervical squamous cell carcinoma and endocervical adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma (PRAD), rectum adenocarcinoma (READ), uterine corpus endometrial carcinoma and uterine carcinosarcoma, with PRAD and READ exhibiting the highest expression of all cancers. CTSL was upregulated in lymphoid neoplasm diffuse large B-cell lymphoma, oesophageal carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, lower grade glioma, pancreatic adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, and thymoma. Hypo-methylation of both genes was evident in most cases where they have been highly upregulated. We have expanded on our observations by including data relating to mutations and copy number alterations at pan-cancer level. The novel hypotheses that are stemming out of these data need to be further investigated and validated in large clinical studies.

Type 2 inflammation modulates ACE2 and TMPRSS2 in airway epithelial cells

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically changed our world, country, communities, and families. There is controversy regarding risk factors for severe COVID-19 disease. It has been suggested that asthma and allergy are not highly represented as comorbid conditions associated with COVID-19.ObjectiveOur aim was to extend our work in IL-13 biology to determine whether airway epithelial cell expression of 2 key mediators critical for SARS-CoV-2 infection, namely, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), are modulated by IL-13.MethodsWe determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. We also examined expression of ACE2 and TMPRSS2 in 2 data sets containing gene expression data from nasal and airway epithelial cells from children and adults with asthma and allergic rhinitis.ResultsIL-13 significantly reduced ACE2 and increased TMPRSS2 expression ex vivo in airway epithelial cells. In 2 independent data sets, ACE2 expression was significantly reduced and TMPRSS2 expression was significantly increased in the nasal and airway epithelial cells in type 2 asthma and allergic rhinitis. ACE2 expression was significantly negatively associated with type 2 cytokines, whereas TMPRSS2 expression was significantly positively associated with type 2 cytokines.ConclusionIL-13 modulates ACE2 and TMPRSS2 expression in airway epithelial cells in asthma and atopy. This deserves further study with regard to any effects that asthma and atopy may render in the setting of COVID-19 infection.

Dexmedetomidine promotes breast cancer cell migration through Rab11-mediated secretion of exosomal TMPRSS2.

BackgroundDexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, has been reported to increase the malignancy of breast cancer cells in vitro and stimulate tumor growth in mice. Transmembrane protease serine 2 (TMPRSS2) demonstrates proteolytic activity, resulting in degradation of the extracellular matrix (ECM). This study investigated whether and how TMPRSS2 regulates migration of DEX-treated breast cancer cells.MethodsBreast cancer cell lines MCF-7 and MDA-MB-231 were treated with DEX and scratch assay was performed. Expressions of TMPRSS2, α2-adrenergic receptor, phospho-STAT3Tyr705, Rab11, and ECM components were assessed using real-time polymerase chain reaction (real-time PCR), Western blotting, and immunofluorescence staining. ELISA and ultracentrifugation were used to quantify secreted exosomal proteins. Knockdown assay was used to inhibit the expression of TMPRSS2 and Rab11.ResultsDEX significantly increased the migration of MCF-7 and MDA-MB-231, which was accompanied by the upregulation and colocalization of TMPRSS2 and α2-adrenergic receptor. Nuclear phospho-STAT3Tyr705 was increased dramatically following DEX treatment, and TMPRSS2 upregulation was significantly suppressed by the STAT3 inhibitor WP1066. Meanwhile, TMPRSS2 knockdown decreased DEX-induced cellular migration. TMPRSS2 and Rab11 were significantly detected in the media and the isolated exosomes from DEX-treated cells, and their colocalization was also revealed. Rab11 knockdown prevented exosomal TMPRSS2 from increasing in DEX-treated cells. In normal cultured MDA-MB-231, migration was increased by Rab11-positive exosomes isolated from DEX-treated MCF-7. Moreover, transmission electron microscopy showed that Rab11-positive exosomes enriched more components than Rab11-negative exosomes. Additionally, a reduction in ECM components fibronectin, collagen IV, matrix metallopeptidase 16, and Tenascin C was detected after DEX treatment, but was prohibited when TMPRSS2 or Rab11 were knocked down.ConclusionsThis study provides evidence that DEX upregulates TMPRSS2 expression via the activation of α2-adrenergic receptor/STAT3 signaling and promotes TMPRSS2 secretion in exosomes through Rab11, thus resulting in degradation of the ECM, which is responsible for DEX-induced migration of breast cancer cells.

SARS-CoV-2 Related Protein Expression may Predict Vulnerability for Developing COVID-19 in Cancer Patients

Dear Editor, Ongoing epidemic of Coronavirus disease (COVID-19) has presented new challenges to the oncologists. Recent studies have suggested higher COVID-19 related mortality in cancer patients (1), reasons for which are currently little understood. Although, COVID-19 primarily causes acute respiratory distress syndrome (ARDS), widespread inflammation and multi-organ dysfunction are common in progressed disease. Increased fragility, age associated factors, and organ specific or systemic dysfunctions in cancer patients may add to the COVID-19 related pathology increasing the chances of mortality (2). Apart from these obvious risk factors, whether there is a cancer specific vulnerability to COVID-19 is scarcely reported. COVID-19 is caused by a new coronavirus strain ‘Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)’ from the family of betacoronaviruses. SARS-CoV-2 binds to angiotensin converting enzyme 2 (ACE2) protein present on the surface of human epithelial cells which facilitates its entry inside the cell (3). For ACE2 mediated cell entry of the SARS-CoV-2 co-expression of proteases like—Transmembrane protease, serine 2 (TMPRSS2), Cathepsin-L (CTSL) and Furin are essential (3). An analysis of tissue specific expression of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2/CTSL/Furin in human cancer patients can inform on their vulnerability for developing COVID-19. We performed in silico analysis of open access data for SARS-CoV-2 related proteins available on Human Protein Atlas (https://www.proteinatlas.org/humanproteome/sars-cov-2). Human Protein Atlas is a standard database for protein expression in normal and pathological human tissues including 20 different types of cancer (4).The details of the laboratory and statistical methods used to generate expression data used for this study is available on https://www.proteinatlas.org/about/assays+annotation. We noted high tissue expression of the viral entry factors in certain specific cancers (Fig. 1). ACE2 expression was detected in many but was specifically enhanced in renal cancer (detected in 100% of cases) (Fig. 1a&b), and had significant expression in colorectal, gastric, and pancreatic cancers (Fig. 1b). All these cancers also had significant expression of TMPRSS2, CTSL, and Furin (Fig. 1b). Higher expression of ACE2 is regarded favourable for the renal cancer, however it may also make patients vulnerable to SARS-CoV-2 infection (4) with an increased chance of renal dysfunction in COVID-19 (5). Uniquely, prostate cancer patients had highest TMPRSS2 RNA expression. TMPRSS2 is an androgen regulated gene and inhibition of TMPRSS2 using androgen-deprivation therapies (ADTs) has been shown to block or decrease the severity of SARS-CoV2 infections (6). A SARS-CoV-2 cell entry factors based vulnerability for developing COVID-19 appears higher in patients of renal and prostate cancers, however this needs to be investigated further. A conclusive knowledge in this regard can help in prevention and therapeutic management of COVID-19 in these patients. Conflict of Interest Authors declare no conflict of interest. "Data accessibility" statement Data related to this manuscript can be accessed from the corresponding author on a reasonable request.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature