Breaking News! Chinese Researchers Discover circRNAs Encoded By SARS-CoV-2 Virus That Can Cause Cancer! Millions Expected To Get Cancer Eventually!

SARS-CoV-2 And Cancer: A new study by Chinese researchers from Hunan University has found the presence of thousands of viral proteins known as circRNAs encoded by the SARS-CoV-2 coronavirus with some that have the potential to trigger cellular and genetic reactions that can lead to cancer ultimately.


 
It is already known that the life-threatening coronaviruses MERS-CoV, SARS-CoV-1 and SARS-CoV-2 (SARS-CoV-1/2) have caused and will continue to cause enormous morbidity and mortality to humans.
 
Virus-encoded noncoding RNAs are poorly understood in coronaviruses. Data mining of viral-infection-related RNA-sequencing data has resulted in the identification of 28 754, 720 and 3437 circRNAs encoded by MERS-CoV, SARS-CoV-1 and SARS-CoV-2, respectively.
 
Interestingly MERS-CoV exhibits much more prominent ability to encode circRNAs in all genomic regions than those of SARS-CoV-1/2. Viral circRNAs typically exhibit low expression levels. Moreover, majority of the viral circRNAs exhibit expressions only in the late stage of viral infection.
 
Detailed analysis of the competitive interactions of viral circRNAs, human miRNAs and mRNAs in MERS-CoV infections reveals that viral circRNAs up-regulated genes related to mRNA splicing and processing in the early stage of viral infection, and regulated genes involved in diverse functions including cancer, metabolism, autophagy, viral infection in the late stage of viral infection.
 
Also similar analysis in SARS-CoV-2 infections reveals that its viral circRNAs down-regulated genes associated with metabolic processes of cholesterol, alcohol, fatty acid and up-regulated genes associated with cellular responses to oxidative stress in the late stage of viral infection.
 
A few genes regulated by viral circRNAs from both MERS-CoV and SARS-CoV-2 were enriched in several biological processes such as response to reactive oxygen and centrosome localization.
 
This study provides the first glimpse into viral circRNAs in three deadly coronaviruses and would serve as a valuable resource for further studies of circRNAs in coronaviruses.
 
It also provides a warning about potential cancers that could ultimaltely develop in millions of so called ‘recovered’ COVID-19 patients!
 
The study findings were published in the Oxford Academic peer reviewed journal: Briefings in Bioinformatics.
https://academic.oup.com/bib/article/22/2/1297/6015892
 
To date, the COVID-19 pandemic caused by the SARS-CoV-2 has claimed more than 2.8 million lives. SARS-CoV-2 belongs to the Coronaviridae family, which contains a positive and single-stranded RNA genome. In addition to SARS-CoV-2, researchers have reported the presence of six potential coronaviruses that can infect the human population.
 
Between 2002–2004, SARS-CoV-1 had claimed over 900 lives across 32 countries. MERS-CoV had been also reported to cause epidemics in over 20 countries, since 2012. The data up to January 2020 revealed that this virus had already caused 866 deaths.
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By analyzing this data, researchers concluded that coronaviruses have a high mortality rate and are life-threatening to humans.
 
Typically coronaviruses contain large RNA genomes and are categorized into four genera, namely, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.
 
Importantly the SARS-CoV-1, SARS-CoV-2, and MERS-CoV belong to the genera Betacoronavirus, which contains open reading frames (ORFs). These ORFs encode nonstructural proteins (nsps), and structural proteins such as spike (S), envelope (E), membrane (M), nucleocapsid (N), and accessory proteins. An extensive body of research has revealed that virus-encoded noncoding RNAs play a crucial role in the infection process. The identification of noncoding RNAs in coronaviruses therefore plays a significant role in understanding the complex transcription process.
 
It should be noted that the circular RNAs (circRNAs) are reported to possess varied functions in mammals and plants. These are covalently closed long noncoding RNAs that lack a 3’ poly(A) tail and 5’ cap. The diverse functions of circRNAs are owing to the presence of multiple protein binding sites. It also encodes proteins and interacts with other proteins as a part of its varied functions. For instance, circFOXO3 can inhibit the process of the cell cycle by binding to cyclin-dependent kinase 1 and cyclin-dependent kinase 2 during the cell cycle.
 
Past research has revealed that several viral circRNAs, such as hpv-circE7, ebv-circRPMS1, and ebv-circLMP2A, are associated with the development of cancers. Scientists have identified and characterized circRNAs from cancer-associated viruses, namely, Epstein–Barr virus and the Kaposi’s sarcoma herpesvirus. However, there is a research gap in regards to circRNAs in coronaviruses.
 
This new research has alarmingly identified thousands of circRNAs in Betacoronaviruses, including MERS-CoV, SARS-CoV-1, and SARS-CoV-2, from the RNA-sequencing data of viral infections. These coronaviruses have a similar genomic structure with a diverse circRNA coding ability.
 
These viral circRNAs can function as microRNA (miRNA) sponges, by binding proteins, or by encoding proteins. For example, ciRS-7 contains more than 70 binding sites for miR-7 and correlates with the human disease by affecting miR-7 activity.
 
The circRNAs can also function by encoding proteins or interacting with proteins . For example, circFOXO3 binds to the cell cycle proteins cyclin-dependent kinase 2 and cyclin-dependent kinase inhibitor 1, which inhibits cell cycle progression. The circRNAs play essential roles in human diseases and are considered to be ideal biomarkers of these diseases due to their high stability. For example, the up-regulation of hsa_circ_0000064 has been reported in lung cancer tissues and cell lines. Knockdown of hsa_circ_0000064 can attenuate the proliferation, block cell cycle progression, promote cell apoptosis, abate migration and invasion activities of lung cancer cell lines, which indicate this circRNA is a potential prognostic biomarker for lung cancer.
 
In recent years, virus-encoded circRNAs have been identified and characterized in several cancer-associated viruses such as the Epstein–Barr virus and the Kaposi’s sarcoma herpesvirus.
 https://pubmed.ncbi.nlm.nih.gov/30080890/
 
https://pubmed.ncbi.nlm.nih.gov/30150410/
 
https://pubmed.ncbi.nlm.nih.gov/30710798/
 
Several viral circRNAs were associated with the progression of cancers, such as hpv-circE7, ebv-circRPMS1 and ebv-circLMP2A. https://pubmed.ncbi.nlm.nih.gov/31127091/
 
https://pubmed.ncbi.nlm.nih.gov/31695488/
 
https://pubmed.ncbi.nlm.nih.gov/32790025/
 
A recent study by systematically investigated circRNAs in viruses and identified more than 10 000 circRNAs . These circRNAs are encoded in more than 20 viruses including several RNA viruses and RT viruses, which suggest the circRNAs may be a kind of widespread molecules in viruses. https://academic.oup.com/bib/article-abstract/22/2/2182/5826501
 
However, no circRNAs from coronaviruses have been reported so far.
 
This is the first study that has identified thousands of circRNAs in MERS-CoV and SARS-CoV-1/2 from the RNA-sequencing data of viral infection. 
 
The study team has also systematically characterized circRNAs in coronaviruses, with regard to their size, sequence feature, expressions, genome, location preference, and functions. This opens the door to further explore and understand the mode of action of individual circRNAs in coronaviruses.
 
The team reported that MERS-CoV encodes more than 20,000 viral circRNAs, which is significantly more than SARS-CoV-1 and SARS-CoV-2. Researchers have also found that even though SARSCoV-1 and SARS-CoV-2 share 80% genomic similarity, there is a difference in the number of viral circRNAs.
 
Past research had revealed that the genome size of viruses had a weak correlation with the coding ability of circRNAs. Such connections are not found in varied genomic types, including circular or linear genomes.
 
Importantly another reason which contributes to the varied ability of viruses in encoding circRNAs is the influence of the RNA-binding proteins (RBPs). The dynamic expression of viral circRNAs is because RBPs proteins, which produce circRNAs, are dynamically regulated by viral infections. Scientists have reported that more than 30% of circRNAs are vigorously controlled by the alternative splicing factor. Researchers believe that more study is required to determine the coding ability of circRNAs in viruses.
 
It was found that the majority of viral circRNAs identified in this study are encoded by the negative strand of the coronaviruses. Thereby, the current study highlights that more research is required to understand the mechanism of generating circRNAs in the negative-strand of coronaviruses.
 
It is also important to note that the role of viral circRNAs in viral infection is also a less explored area of research. The current research shows circRNAs may act as a sustained effector in cellular signaling pathways due to their unique structure and increased stability.
 
Interestingly most of the coronavirus circRNAs, identified in this study, expressed in the later stage of infection. In the early stage of MERS-CoV infection, viral circRNAs were observed to up-regulate genes related to mRNA splicing and processing.
 
Alarmingly the viral circRNAs were found to regulate genes involved in diverse functions such as cancer, metabolism, autophagy, etc., in the late stage of viral infection. In the case of SARS-CoV-2, genes down-regulated by viral circRNAs were linked with metabolic processes of cholesterol, alcohol, etc., and up-regulated genes were involved with functions such as cellular responses to oxidative stress in the late stage of viral infection.
 
A key limitation of this study is that the identification of viral circRNAs has solely been conducted by computational methods. Further experimental validation of their presence is required. Despite the limitations, this study identifies and characterizes a range of circRNAs encoded by MERS-CoV, SARS-CoV-1, and SARS-CoV-2. Thereby, it provides a valuable resource for further research of circRNAs in coronaviruses.
 
The implications of this study are alarming as it means that we will be anticipating a huge number of cancer patients in coming months and years considering that hundreds of millions of people around the world have been exposed to the SARS-CoV-2 coronavirus.
 
Thailand medical news had already given forewarnings on the cancer risk posed by the new SARS-CoV-2 coronavirus as early as August 2020. https://www.thailandmedical.news/news/must-read-covid-19-questions-can-the-sars-cov-2-coronavirus-ultimately-also-cause-cancer
 
Read Also: https://www.thailandmedical.news/news/covid-19-and-cancer-study-shows-that-sars-cov-2-and-usage-of-anti-covid-19-drugs-can-reactivate-oncogenic-viruses-and-increase-risk-of-cancer
 
We will be providing more studies on the relationship between cancer and SARS-CoV-2 coronavirus in coming weeks.
 
For more on SARS-CoV-2 and Cancer, keep on logging to Thailand Medical News.