A new bioinformatics study has alarmingly found individuals infected with the SARS-CoV-2 coronavirus have an upregulation of various oncogenic genes especially in the peripheral blood mononuclear cells (PBMCs).
The study findings suggested that SARS-CoV-2 can be considered a potential risk factor for increasing the probability of developing cancer.
The study findings were published on a peer review platform: Research Square, and are currently being peer reviewed.
Although the SARS-CoV-2 predominantly is a pulmonary disease (17), but other complications such as heart failure, brain damage and kidneys impairment have been reported (18–20). To date, limited studies have described SARS-CoV-2 as a potential risk factor for developing cancer.
Former analysis on transcriptomic databases suggested that SARS-CoV-2 induces the expression of the host transcription factors which also could be identified in NHBE, A549, and Calu-3 lung cancer cell lines. In the course of SARS‑CoV‑2 invasion host immune checkpoints and cytokine pathways such as programmed death ligand 1 (PDL1), PDL2, interleukin 6 (IL‑6), type II interferon, and NF-Kappa B (NF-κB) are activated in order to wipe-out the infection.
These pathways also manifested in cancer cell lines similar to host reaction against SARS‑CoV‑2 (2). Another bioinformatic study analyzed the gene expression pattern of 10 most life-threatening cancers. The TCGA database results demonstrated up-regulation of CREB1, PTEN, SMAD3, and CASP3 genes in pancreatic adenocarcinoma.
Based on their conclusion, SARS-CoV-2 potentially could induce the expression of these genes through interaction with angiotensin-converting enzyme 2 (ACE2) on the cell surface of pancreatic cells (6). Also, it has been suggested that SARS-CoV-2 is involved in tumorigenesis mechanisms that control cell proliferation, death, migration as well as immune system responses (7).
However, due to the complexity of SARS-CoV-2 pathogenicity, the long-term health consequences demand more investigations. In this context, our analysis revealed that the up-regulated genes in COVID-19 is similar to cancer processes at least in three different categories including: cell cycle regulation, viral carcinogenesis, and cellular senescence.
The most characteristic feature of cancer development is dysregulation of the cell cycle machinery (21). The cell cycle regulatory mechanism is tightly associated with the cellular processes of proliferation, differentiation, and apoptosis (22). Any disruption in the cell cycle regulation leads to molecular changes that results in aberrant biological behavior of cancer cells (23).
This includes resistance to DNA damages, apoptosis and anti-mitotic programs as well as activation of oncogenes or deactivation of tumor suppressor genes that are mediated by cell cycle regulatory mechanisms (24). Accordingly, 17 cell cycle-related genes were up-regulated in SARS-CoV-2 patients including: CCNB2, ESPL1, TTK, CCNA2, CCNB1, CDC6, CDC20, CDK1, BUB1, CHEK1, BUB1B, CDC45, PLK1, CCNA1, ORC1 AND E2F1.
Any dysregulation in the expression of these genes is linked with various cancers, such as breast cancer, digestive tract cancer, bone cancer, endometrial cancer, skin cancer, brain cancer, lung cancer and so on. For example, the cyclin B2 (CCNB2) is a cell cycle regulator and a member of B-type cyclins superfamily (25). CCNB2 deficiency causes the G2/M checkpoint to fail during the cell cycle, resulting in gene mutations and cancer (26).
The role of CCNB2 in the development of various cancers and metastatic conditions has also been documented. Its overexpression is associated with poor prognosis in hepatocellular carcinoma (HCC) patients (27). Also, targeting CCNB2 via miR-582-3p seems to inhibit the proliferation of acute myeloid leukemia (28). An up-regulated expression of CCNB2 was noted in human triple-negative breast cancer (TNBC) cells which ultimately contributed to some pathological features in TNBC patients. In addition, CCNB2 increases the proliferation of TNBC cells In Vitro and causes TNBC tumors in mice (29).
Viruses are one of the well-known causes of various malignancies in human (30). Thus far, seven human oncoviruses have been associated with malignancies. These include high-risk types of human papilloma virus (HPV), hepatitis B and hepatitis C viruses (HBV and HCV), Epstein-Barr virus (EBV) and Kaposi’s Sarcoma-Associated Herpesvirus (KSHV), Merkel cell polyomavirus (MCPyV), and human T-cell leukemia virus I (HTLV-1) (31).
The pathophysiology of this carcinogenic potential in viruses affecting humans is not fully understood. It seems, oncogenic viruses share similar characteristics that enable them to cause cancer (32). In this regard, our analysis provided 12 up-regulated genes with possible relation to viral carcinogenesis in SARS-CoV-2 blood sample, including: H4C8, H2BC7, CDC20, H2BC5, CDK1, H2BC17, H2BC9, CHEK1, EIF2AK2, CCNA1, H2BC8 and CCNA2.
For the most part, these genes contribute to viral replication. However, dysregulation in expression of these genes could disrupt cellular processes such as apoptosis and cell-cycle checkpoints that consequently leads to malignancy (4, 5). Cell division cycle 20 (CDC20) is a regulatory protein that interacts with the cell cycle’s anaphase-promoting complex/cyclosome (APC/C) and plays a crucial role in carcinogenesis and cancer progression (33).
Upregulation of CDC20 has been shown in various malignancies including pancreatic ductal adenocarcinoma (34), oral squamous cell carcinoma (35), gastric cancer (36), cervical cancer (37) and hepatocellular carcinoma (38). In a previous study, CDC20 was implicated as an oncoprotein promoting the proliferation of cancer cells (39). In addition, targeting CDC20 hinders the mitosis process in cancer cells. This may seem better treatment option than traditional spindle-perturbing medicines for curing cancer (40).
In another study, up-regulation of CDC20 was associated with proliferation of Hepatocellular carcinoma cells and in vitro siRNA-mediated knockdown of CDC20 was shown to restrict HCC progression (41). Furthermore, the suppression of CDC20 is linked with p21 activation, which in turn impedes the cell cycle through inhibition of G2/M CDKs activity and transcriptional activation of E2F (42, 43).
Cellular senescence plays a crucial role in preventing cancer development (44). Senescence is a protecting factor against cancer development that is induced by mutations in oncogenes or the DNA damage (45, 46). The senescence rate was found to be high in premalignant conditions and low in invasive lesions (47).
Mutations in key oncogenes may lead to senescence which consequently destroys premalignant cells before becoming invasive (48). Therefore, curbing the process of senescence is a major contributor to invasive cancer development from pre-malignant lesions (49). It is suggested that the loss of one of the essential senescence effectors such as p53 might be a cause for senescence failure (50).
As a result of this deficiency, the oncogene promotes the cancer growth, inexorably. The immune anti-tumor response elicited by senescent cells is known as “senescence surveillance” (51). In contrast, in certain instances, stromal cell senescence seems to promote tumor development. This might be due to the proangiogenic effects of particular senescence-associated secretory phenotype (SASP) components such as vascular endothelial growth factor (VEGF), or the impact of senescent fibroblasts on the surrounding tumor cells (44).
It is also evident that the “immune senescence” or the aging of the immune system as people become older, may cause the failure of immune surveillance leading to the development of cancer in the elderly. This phenomenon was researched in peripheral blood T cells with telomere shortening and its association with cancer development (52).
There are multiple factors and molecules involved in the senescence signaling. These include various oncogenes and tumor suppressors that may be up or down regulated as part of the carcinogenic process, making the identification of senescence difficult (46). In SARS-CoV-2 patients, we found 10 up-regulated genes which take part in the senescence which were: CCNB1, FOXM1, CCNB2, CDC25A, CDK1, CHEK1, CCNA1, E2F1, CCNA2 AND MYBL2.
In the aforementioned list, cell cycle checkpoint kinase 1 (CHEK1) is a conserved protein kinase that acts as a limiting agent in the cell cycle. CHEK1 is generally inactive in the absence of DNA damage, it is mainly activated by ATM in response to double-strand DNA breaks, and its activation involves dimerization and autophosphorylation (53).
To sum up, CHEK1 is one of the most important speed limiting factors in the cell cycle and its overexpression may promote the development of human malignant tumors, such as lung, bladder, colon, stomach, ovarian, and cervical cancers (54).