Chronic hexavalent chromium exposure upregulates the RNA methyltransferase METTL3 expression to promote cell transformation, cancer stem cell-like property, and tumorigenesis.

Details

• Personal Author:
  Kondo K ; Tao H ; Uddin MB ; Wang Z ; Xie J ; Yang C ; Zeidler-Erdely PC
• Description:
  Hexavalent chromium [Cr(VI)] is a common environmental carcinogen causing lung cancer in humans. This study investigates the mechanism of Cr(VI) carcinogenesis focusing on the role of the epitranscriptomic dysregulation. The epitranscriptomic effect of Cr(VI) was determined in Cr(VI)-transformed human bronchial epithelial cells, chromate-exposed mouse and human lungs. The epitranscriptomic effect and its role in Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis were determined by microarray analysis, soft agar colony formation, suspension spheroid formation and mouse xenograft tumorigenesis assays. It was found that chronic Cr(VI) exposure causes epitranscriptomic dysregulations as evidenced by the increased levels of total RNA N6-methyladenosine (m6A) modification and the RNA m6A methyltransferase METTL3 in Cr(VI)-transformed cells and chromate exposure-caused mouse and human lung tumors. Knockdown of METTL3 expression in Cr(VI)-transformed cells significantly reduces their m6A levels and transformed phenotypes and tumorigenicity in mice. Moreover, knockdown of METTL3 expression in parental non-transformed cells significantly reduces the capability of chronic Cr(VI) exposure to induce cell transformation and CSC-like property. Together, this study reveals that chronic Cr(VI) exposure is capable of altering cellular epitranscriptome by increasing the m6A RNA modification via upregulating the RNA methyltransferase METTL3 expression, which plays an important role in Cr(VI)-induced cell transformation, CSC-like property and tumorigenesis. [Description provided by NIOSH]
• Subjects:
  Animals Carcinogens Chromium Environmental Exposure Laboratories Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Risk Assessment Risk Factors Safety

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• Keywords:
  Author Keywords: Cancer Stem Cell (CSC)-like Property; Epitranscriptome; Hexavalent Chromium; METTL3; RNA Modification; M6A Hexavalent Chromium; Carcinogens; Environmental Exposure; Lung Cancer; Humans; Carcinogenesis; Animals; Laboratory Animals; Tumorigenesis; RNA; Ribonucleic Acids; Exposure Levels; Risk Factors;
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Kentucky ; Ohio ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 5 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  51-61
• Volume:
  187
• Issue:
  1
• NIOSHTIC Number:
  nn:20064774
• Citation:
  Toxicol Sci 2022 May; 187(1):51-61
• Contact Point Address:
  Chengfeng Yang, Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109, United States
• Email:
  chengfeng.yang@case.edu
• CAS Registry Number:
  Chromium(6+) (CAS RN 18540-29-9)
• Federal Fiscal Year:
  2022
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Toxicological Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d54f794ece1b8c8f2d8ddf42ab94349000d34bfd9e97cae12edd10b5296133f9dac008c3669930b2a075de42ed6f92eb3eeca22a99ad3e118f71400bc8259259
• Download URL:
  https://stacks.cdc.gov/view/cdc/248756/cdc_248756_DS1.pdf
• File Type:
  [PDF - 832.91 KB ]