The pivotal regulatory factor circBRWD1 inhibits arsenic exposure-induced lung cancer occurrence by binding mRNA and regulating its stability

Abstract

Multiple studies have indicated that circular RNAs (circRNAs) play a regulatory role in different stages of tumors by interacting with various molecules. With continuous in-depth research on the biological functions of circRNAs, increasing evidence has shown that circRNAs play important roles in carcinogenesis caused by environmental pollutants. However, the function and mechanism of circRNAs in arsenic exposure-induced lung cancer occurrence have not been reported. In this study, RNA sequencing and qPCR assays revealed that the expression of circBRWD1 was decreased in BEAS-2B-As cells and multiple lung cancer cell lines. Silencing circBRWD1 promoted cell viability and proliferation, inhibited cell apoptosis, and accelerated the G0/G1 phase transition in BEAS-2B-As cells; however, these functions were abrogated by circBRWD1 overexpression. Mechanistically, under arsenic exposure, expression of decreased circBRWD1 led to enhanced stability of the mRNA to which it directly binds (c-JUN, c-MYC, and CDK6 mRNA), increasing its expression. This mechanism promotes the malignant transformation of lung cells and ultimately leads to lung cancer. Our findings thus reveal the molecular mechanism of arsenic carcinogenesis. Multiple studies have indicated that circular RNAs (circRNAs) play a regulatory role in different stages of tumors by interacting with various molecules. With continuous in-depth research on the biological functions of circRNAs, increasing evidence has shown that circRNAs play important roles in carcinogenesis caused by environmental pollutants. However, the function and mechanism of circRNAs in arsenic exposure-induced lung cancer occurrence have not been reported. In this study, RNA sequencing and qPCR assays revealed that the expression of circBRWD1 was decreased in BEAS-2B-As cells and multiple lung cancer cell lines. Silencing circBRWD1 promoted cell viability and proliferation, inhibited cell apoptosis, and accelerated the G0/G1 phase transition in BEAS-2B-As cells; however, these functions were abrogated by circBRWD1 overexpression. Mechanistically, under arsenic exposure, expression of decreased circBRWD1 led to enhanced stability of the mRNA to which it directly binds (c-JUN, c-MYC, and CDK6 mRNA), increasing its expression. This mechanism promotes the malignant transformation of lung cells and ultimately leads to lung cancer. Our findings thus reveal the molecular mechanism of arsenic carcinogenesis. IntroductionIn 2020, the authoritative cancer report of the International Agency for Research on Cancer (IARC) showed that the mortality and morbidity of lung cancer in the world rank first and second, respectively, among all malignant tumors, while death from lung cancer and new lung cancer cases rank first among all malignant tumors in China, seriously endangering human life and health.1Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA. Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (17778) Google Scholar However, to date, the pathogenesis of lung cancer is still unclear, with many factors playing specific roles in the pathogenesis of lung cancer. Hence, lung cancer is the comprehensive result of many factors. In addition to smoking, family cancer history, respiratory diseases, and other factors, environmental chemical carcinogen exposure is an important factor in lung cancer occurrence.Arsenic is one of the most common environmental pollutants, occurring naturally in rocks, soil, and water. Arsenic is also a known human carcinogen that exists in nature and is toxic to humans, leading to various adverse effects and diseases.2Naujokas M.F. Anderson B. Ahsan H. Aposhian H.V. Graziano J.H. Thompson C. Suk W.A. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem.Environ. Health Perspect. 2013; 121: 295-302Crossref PubMed Scopus (816) Google Scholar In contaminated environments, arsenic contributes to harmful effects on an increasing number of people.3Maheshwari N. Khan F.H. Mahmood R. Sodium meta-arsenite induced reactive oxygen species in human red blood cells: impaired antioxidant and membrane redox systems, haemoglobin oxidation, and morphological changes.Free Radic. Res. 2017; 51: 483-497Crossref PubMed Scopus (11) Google Scholar Exposure to arsenic causes cardiovascular disease,4Karachaliou C. Sgourou A. Kakkos S. Kalavrouziotis I. Arsenic exposure promotes the emergence of cardiovascular diseases.Rev. Environ. Health. 2021; https://doi.org/10.1515/reveh-2021-0004Crossref PubMed Scopus (2) Google Scholar diabetes N. R. J. C. R. M. M. arsenic exposure and a and PubMed Scopus Google Scholar and lung S. H. S. of arsenic exposure and lung Res. Google Scholar and H. J. of arsenic and human 2021; PubMed Scopus Google Scholar exposure to arsenic result in C. S. M. of arsenic for Cancer PubMed Scopus Google Scholar and of to of Health Perspect. PubMed Scopus Google Scholar Arsenic carcinogenesis by cell proliferation, apoptosis, and N. S. of arsenic in proliferation, and Environ. 2021; PubMed Scopus Google Scholar evidence that arsenic not stability also promotes by in expression in cancer and other PubMed Scopus Google Scholar and J. J. M. J. S. H. of promotes in induced by arsenic 2021; Scopus Google Scholar With a of studies have that circular RNAs (circRNAs) function of in C. J. B. F. H. from of is in the malignant transformation of human cells by the cell and cell PubMed Scopus Google from a of regulatory The by a with and A. A. M. C. from of its mRNA 2017; PubMed Scopus Google Scholar circRNAs in biological the cell cell and and circular PubMed Scopus Google Scholar circRNAs function a that binds to and This is in a and cancer cell and circRNAs in transition H. B. RNA promotes and transition of cell lung cancer cells by 2021; PubMed Scopus Google Scholar studies have shown that chronic arsenic exposure to the malignant transformation of cells by the of was and in the of carcinogenesis in an C. J. B. F. H. from of is in the malignant transformation of human cells by the cell and cell PubMed Scopus Google Scholar arsenic to and increasing thus malignant J. C. F. H. of is in the transition malignant transformation of human PubMed Scopus Google Scholar the mechanism which arsenic circRNAs and contributes to molecular of function have been revealed an and mRNA expression B. J. RNA function 2013; PubMed Scopus Google Scholar circRNAs with that that in cell proliferation, and and circular RNA cell with and Res. PubMed Scopus Google M. promotes cancer by to 2021; PubMed Scopus Google Scholar circRNAs directly that in the of biological functions by M. S. C. F. N. H. role of circular RNA in Cancer Scopus Google M. N. J. S. F. H. by the circular of the PubMed Scopus Google Scholar The for this is a of mRNA this regulatory mechanism has been with studies on arsenic carcinogenesis. circRNAs on circRNAs directly to the is this circRNAs function by directly and to expression. The function of circBRWD1 has not been The revealed that circBRWD1 is in human cells and multiple lung cancer cells that the of The of circBRWD1 to the of lung cancer. 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Clin. 2021; 71: 209-249Crossref PubMed Scopus (17778) Google Scholar However, the lung cancer have not been in RNA research has that RNAs in the of lung J. C. J. B. a an role in lung cancer with to 2021; PubMed Scopus Google S. in lung and PubMed Scopus Google Scholar The expression and of circRNAs and cell which and specific other J. specific of circular RNA 2013; PubMed Google J. A. the RNA from to 2017; PubMed Scopus Google J. RNAs and with 2013; PubMed Scopus Google Scholar number of circRNAs have been and to in the of an increasing of evidence has shown that circRNAs play important roles in the carcinogenesis induced by environmental J. M. C. F. H. B. of is in the of by human in PubMed Google F. S. S. J. of of Res. PubMed Scopus Google Scholar has been that chronic arsenic exposure in the malignant transformation of cells by is in the malignant transformation of human and C. J. B. F. 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R. and induced by arsenic in 2013; PubMed Scopus Google Scholar Arsenic exposure-induced malignant transformation of cells accelerated the cell promoted cell proliferation, the and inhibited H. C. S. J. expression of and its of and is with malignant transformation of human Environ. 2021; PubMed Scopus Google Scholar Arsenic exposure the J. M. S. arsenic exposure and in human cells the Health Perspect. PubMed Scopus Google Scholar I. of the 2013; PubMed Scopus Google Scholar and J. J. C. S. H. of in and cells the and PubMed Scopus Google Scholar with other that carcinogenesis. arsenic exposure to malignant transformation and in expression in cancer and other PubMed Scopus Google Scholar studies have shown that arsenic cancer by the expression of that arsenic exposure the expression of which the expression of the which in and the cell and leading to malignant cell J. F. H. 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Google Scholar evidence that circRNAs the occurrence and of cancer c-MYC, and Our research revealed that circBRWD1 directly binds to mRNA (c-JUN, c-MYC, and CDK6 and its circBRWD1 with c-MYC, and CDK6 was in the malignant transformation of The cell was the of these cells and that a of circBRWD1 expression the cell by the stability of c-MYC, and CDK6 the of lung cancer cancer is the of death worldwide and has thus been a of cancer Exposure to environmental chemical is an important factor in molecular is of to an increasing number of and date, studies have the function of circRNAs in the of lung cancer caused by arsenic This the function of circRNAs in the of lung cancer caused by arsenic exposure from an of circBRWD1 is under arsenic exposure, which leads to stability of its mRNA (c-JUN, c-MYC, CDK6 mRNA), its the malignant transformation of human and leading to the occurrence of lung cancer circBRWD1 directly and the regulatory factors to mRNA the expression of multiple a that is for the molecular mechanism of lung cancer. the molecular mechanism of regulatory factors in lung cancer new the and of lung and and of an malignant transformation cell cells lung cancer cell and cell and cells were from and of of was with a to the cell and was for and and and was for cell were in a chronic arsenic exposure, cells were to arsenic of arsenic exposure, the cells were The of cell transformation and the of were by a RNA was from and BEAS-2B-As cells and for sequencing the RNAs were in the and with was by and the was to the the were and was and sequencing The were on by and the RNA and RNA was to The and of the RNAs were a and a qPCR was qPCR to on an was the The were by The was to the expression. shown in for circBRWD1 and an were from China, and were was to and and on a for was a to and were to circBRWD1 and were by was cells a to The was by shown in of cell and were and for the circBRWD1 for the and were to were for and were a was to viability cell viability was with a was and with the a of This was to the cells in the and the cells were in this for the was the viability cells were to different of and for and of the was by a RNA and and In the RNA was for a of RNA to RNA and the of to and were with and to the circular of of circBRWD1 was with a specific circBRWD1 with a specific was by The specific circBRWD1 shown in were to with with and with a in for The was to cells for and the was in the was for the were were an to the of and and was a to circBRWD1 expression was to its a while a was to cell with a In were an was by the of cells in the cell the cell was on the of the cell that was in the The were and the was an to were with and with The cell was in and and were and for and in the the of was with with a cells were in was with the cells for The cells were for with in the was a The of cells in the and was and the were and of mRNA (c-JUN, c-MYC, and CDK6 were by cells were in and for circBRWD1 was with and of the of was with a was to was a to were and by The specific shown in cells were in was for for and was to the for cell were and with and and with were to circBRWD1 and its mRNA expression in the circBRWD1 was stability specific number of cells was in a was the cell was RNA was and and was to the RNA was and and the mRNA was by and was to cells and were with a were for to was was with the was to the The membrane was with was with a the of the was with the in The was with and the were with of was by were and a was the the from the IntroductionIn 2020, the authoritative cancer report of the International Agency for Research on Cancer (IARC) showed that the mortality and morbidity of lung cancer in the world rank first and second, respectively, among all malignant tumors, while death from lung cancer and new lung cancer cases rank first among all malignant tumors in China, seriously endangering human life and health.1Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA. Cancer J. Clin. 2021; 71: 209-249Crossref PubMed Scopus (17778) Google Scholar However, to date, the pathogenesis of lung cancer is still unclear, with many factors playing specific roles in the pathogenesis of lung cancer. Hence, lung cancer is the comprehensive result of many factors. In addition to smoking, family cancer history, respiratory diseases, and other factors, environmental chemical carcinogen exposure is an important factor in lung cancer occurrence.Arsenic is one of the most common environmental pollutants, occurring naturally in rocks, soil, and water. Arsenic is also a known human carcinogen that exists in nature and is toxic to humans, leading to various adverse effects and diseases.2Naujokas M.F. Anderson B. Ahsan H. Aposhian H.V. Graziano J.H. Thompson C. Suk W.A. The broad scope of health effects from chronic arsenic exposure: update on a worldwide public health problem.Environ. Health Perspect. 2013; 121: 295-302Crossref PubMed Scopus (816) Google Scholar In contaminated environments, arsenic contributes to harmful effects on an increasing number of people.3Maheshwari N. Khan F.H. Mahmood R. Sodium meta-arsenite induced reactive oxygen species in human red blood cells: impaired antioxidant and membrane redox systems, haemoglobin oxidation, and morphological changes.Free Radic. Res. 2017; 51: 483-497Crossref PubMed Scopus (11) Google Scholar Exposure to arsenic causes cardiovascular disease,4Karachaliou C. Sgourou A. Kakkos S. Kalavrouziotis I. Arsenic exposure promotes the emergence of cardiovascular diseases.Rev. Environ. Health. 2021; https://doi.org/10.1515/reveh-2021-0004Crossref PubMed Scopus (2) Google Scholar diabetes N. R. J. C. R. M. M. arsenic exposure and a and PubMed Scopus Google Scholar and lung S. H. S. of arsenic exposure and lung Res. Google Scholar and H. J. of arsenic and human 2021; PubMed Scopus Google Scholar exposure to arsenic result in C. S. M. of arsenic for Cancer PubMed Scopus Google Scholar and of to of Health Perspect. PubMed Scopus Google Scholar Arsenic carcinogenesis by cell proliferation, apoptosis, and N. S. of arsenic in proliferation, and Environ. 2021; PubMed Scopus Google Scholar evidence that arsenic not stability also promotes by in expression in cancer and other PubMed Scopus Google Scholar and J. J. M. J. S. H. of promotes in induced by arsenic 2021; Scopus Google Scholar With a of studies have that circular RNAs (circRNAs) function of in C. J. B. F. H. from of is in the malignant transformation of human cells by the cell and cell PubMed Scopus Google from a of regulatory The by a with and A. A. M. C. from of its mRNA 2017; PubMed Scopus Google Scholar circRNAs in biological the cell cell and and circular PubMed Scopus Google Scholar circRNAs function a that binds to and This is in a and cancer cell and circRNAs in transition H. B. RNA promotes and transition of cell lung cancer cells by 2021; PubMed Scopus Google Scholar studies have shown that chronic arsenic exposure to the malignant transformation of cells by the of was and in the of carcinogenesis in an C. J. B. F. H. from of is in the malignant transformation of human cells by the cell and cell PubMed Scopus Google Scholar arsenic to and increasing thus malignant J. C. F. H. of is in the transition malignant transformation of human PubMed Scopus Google Scholar the mechanism which arsenic circRNAs and contributes to molecular of function have been revealed an and mRNA expression B. J. RNA function 2013; PubMed Scopus Google Scholar circRNAs with that that in cell proliferation, and and circular RNA cell with and Res. PubMed Scopus Google M. promotes cancer by to 2021; PubMed Scopus Google Scholar circRNAs directly that in the of biological functions by M. S. C. F. N. H. role of circular RNA in Cancer Scopus Google M. N. J. S. F. H. by the circular of the PubMed Scopus Google Scholar The for this is a of mRNA this regulatory mechanism has been with studies on arsenic carcinogenesis. circRNAs on circRNAs directly to the is this circRNAs function by directly and to expression. The function of circBRWD1 has not been The revealed that circBRWD1 is in human cells and multiple lung cancer cells that the of The of circBRWD1 to the of lung cancer. In the findings of this the role of in the occurrence of lung cancer induced by arsenic exposure from the of Our new the molecular mechanism of circRNAs in arsenic carcinogenesis.

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