COVID-19 receptor and malignant cancers: Association of CTSL expression with susceptibility to SARS-CoV-2

Abstract

CTSL is expressed by cancerous tissues and encodes a lysosomal cysteine proteinase that regulates cancer progression and SARS-CoV-2 entry. Therefore, it is critical to predict the susceptibility of cancer patients for SARS-CoV-2 and evaluate the correlation between disease outcomes and the expression of CTSL in malignant cancer tissues. In the current study, we analyzed CTSL expression, mutation rate, survival and COVID-19 disease outcomes in cancer and normal tissues, using online databases. We also performed immunohistochemistry (IHC) to test CTSL expression and western blot to monitor its regulation by cordycepin (CD), and N6, N6-dimethyladenosine (m 6 2 A), respectively. We found that CTSL is conserved across different species, and highly expressed in both normal and cancer tissues from human, as compared to ACE2 or other proteinases/proteases. Additionally, the expression of CTSL protein was the highest in the lung tissue. We show that the mRNA expression of CTSL is 66.4-fold higher in normal lungs and 54.8-fold higher in cancer tissues, as compared to ACE2 mRNA expression in the respective tissues. Compared to other proteases/proteinases/convertases such as TMPRSS2 and FURIN, the expression of CTSL was higher in both normal lungs and lung cancer samples. All these data indicate that CTSL might play an important role in COVID-19 pathogenesis in normal and cancer tissues of the lungs. Additionally, the CTSL-002 isoform containing both the inhibitor_I29 and Peptidase_C1 domains was highly prevalent in all cancers, suggesting its potential role in tumor progression and SARS-CoV-2 entry in multiple types of cancers. Further analysis of the expression of CTSL mutant showed a correlation with FURIN and TMPRSS2, suggesting a potential role of CTSL mutations in modulating SARS-CoV-2 entry in cancers. Moreover, high expression of CTSL significantly correlated with a short overall survival (OS) in lung cancer and glioma. Thus, CTSL might play a major role in the susceptibility of lung cancer and glioma patients to SARS-CoV-2 uptake and COVID-19 severity. Furthermore, CD or m 6 2 A inhibited CTSL expression in the cancer cell lines A549, MDA-MB-231, and/or PC3 in a dose dependent manner. In conclusion, we show that CTSL is highly expressed in normal tissues and increased in most cancers, and CD or m 6 2 A could inhibit its expression, suggesting the therapeutic potential of targeting CTSL for cancer and COVID-19 treatment.

Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies

“…It was reported that SARS-CoV-2 can directly infect and injure many extrapulmonary organs, like the heart, kidney, liver, pancreas, and gastrointestinal tract 18 – 20 , usually with high CTSL expression levels. Besides, the mRNA expression level of CTSL is higher than angiotensin-converting enzyme 2 (ACE2), FURIN, and TMPRSS2 in human lung tissues 21 . Recently, we found that in SARS-CoV-2-infected patients, the circulating blood level of CTSL is highly correlated with the severity and course of COVID-19 symptoms.…”

Immune Profiling Uncovers Memory T-Cell Responses with a Th17 Signature in Cancer Patients with Previous SARS-CoV-2 Infection Followed by mRNA Vaccination

“…Cancer patients are considered a high-risk population for contracting severe COVID-19 disease that could lead to death [ 3 ]. Oncologic patients often present co-morbidities and risk factors associated with COVID-19 severity, including older age, chronic inflammation and genetic alterations associated with severe disease [ 2 , 3 , 4 , 5 ]. Patients with cancer are usually immunocompromised by the disease and antineoplastic treatments [ 3 , 6 , 7 , 8 ].…”

The regulation of ISG20 expression on SARS-CoV-2 infection in cancer patients and healthy individuals

“…The following day, membranes were washed three times with TBST (Tris-buffered saline containing 0.1% Tween20) for 15 min each time, and the blots were incubated with an anti-mouse HRP secondary antibody (1:5000 dilution) in 2% fat-free milk for a further 2 h. Subsequently, the membranes were three times as above. The protocol for western blot in breast cancer tissues and its matched healthy tissues from Chinese breast cancer patients was described previously ( 25 , 26 ). All experiments were repeated three times.…”