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Background <p>High enrichment of N-nitrosamines (NAs) and microcystins (MCs) in drinking water are major risk factors in high-risk areas of esophageal squamous cell carcinoma (ESCC) in China, however, their combined effects and underlying carcinogenic mechanisms remain unknown.</p> Methods <p>The scRNA_seq sequencing and CTD database were used to identify the “chemical-epithelial cell” associated carcinogenic targets. An ESCC rat model was established to confirm the combined effect of NAs and MCs; RNA-Seq was performed to screen potential circRNAs in ESCC and matched adjacent normal tissues. Malignant transformation of esophageal epithelial cells (Het-1A-T) was induced by exposure to N-nitrosomethylbenzylamine (NMBzA) and Microcystin-LR (MC-LR). The biological function of hsa_circ_0063865 was investigated using gain- and loss-of-function experiments in vitro and in vivo. RNA pull-down, ChIRP, RIP, Co-IP and luciferase reporter assays were used to elucidate the underlying mechanisms of hsa_circ_0063865 in chemically related ESCC.</p> Results <p>The rat ESCC model and median-effect principle showed a synergistic effect of NAs and MC-LR in chemical carcinogenesis. Further, integration of single-cell and network toxicology revealed 292 “chemical-epithelial cell” associated carcinogenic targets, which were primarily involved in microRNA in cancer and cytoskeleton rearrangements. At the molecular level, the chemical carcinogenesis-related hsa_circ_0063865 was identified and found to be up-regulated in ESCC tissues. Functionally, hsa_circ_0063865 promoted malignant transformation of Het-1A cells induced by NMBzA and MC-LR by promoting cytoskeletal rearrangements and inhibiting ER stress of MYH9<sup>+</sup> epithelial cell. Mechanistically, hsa_circ_0063865 acted as a modular scaffold to tether eEF1A2(126-177nt of hsa_circ_0063865) and NMIIA (601-658nt of hsa_circ_0063865), thereby promoting NMIIA translation by enhancing the interaction between eEF1A2 and NMIIA, which further promoted cytoskeletal reorganization; Additionally, hsa_circ_0063865 competitively upregulated RCN1 expression by sponging miR-450b-3p, resulting in ER stress inhibition and depolarization of mitochondrial membrane potential via activation of the PERK-eIF2α-ATF4-CHOP axis in MYH9<sup>+</sup> epithelial cell.</p> Conclusion <p>These findings identify a novel chemical carcinogenic target and elucidate the dual-regulatory mechanism of hsa_circ_0063865 in NAs and MC-LR-induced esophageal carcinogenesis.</p>

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hsa_circ_0063865 regulates cytoskeleton rearrangement and endoplasmic reticulum stress to promote esophageal tumorigenesis under co-exposure to N-nitrosamines and microcystin

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Mingjun Sun,
  • Zhikui Gao,
  • Ping Ye,
  • Yuan Ding,
  • Jia Wang,
  • Tingyu Li,
  • Xianghu Wang,
  • Yadong Feng,
  • Lihua Ren,
  • Yong Zhu,
  • Ruihua Shi,
  • Ran Liu

摘要

Background

High enrichment of N-nitrosamines (NAs) and microcystins (MCs) in drinking water are major risk factors in high-risk areas of esophageal squamous cell carcinoma (ESCC) in China, however, their combined effects and underlying carcinogenic mechanisms remain unknown.

Methods

The scRNA_seq sequencing and CTD database were used to identify the “chemical-epithelial cell” associated carcinogenic targets. An ESCC rat model was established to confirm the combined effect of NAs and MCs; RNA-Seq was performed to screen potential circRNAs in ESCC and matched adjacent normal tissues. Malignant transformation of esophageal epithelial cells (Het-1A-T) was induced by exposure to N-nitrosomethylbenzylamine (NMBzA) and Microcystin-LR (MC-LR). The biological function of hsa_circ_0063865 was investigated using gain- and loss-of-function experiments in vitro and in vivo. RNA pull-down, ChIRP, RIP, Co-IP and luciferase reporter assays were used to elucidate the underlying mechanisms of hsa_circ_0063865 in chemically related ESCC.

Results

The rat ESCC model and median-effect principle showed a synergistic effect of NAs and MC-LR in chemical carcinogenesis. Further, integration of single-cell and network toxicology revealed 292 “chemical-epithelial cell” associated carcinogenic targets, which were primarily involved in microRNA in cancer and cytoskeleton rearrangements. At the molecular level, the chemical carcinogenesis-related hsa_circ_0063865 was identified and found to be up-regulated in ESCC tissues. Functionally, hsa_circ_0063865 promoted malignant transformation of Het-1A cells induced by NMBzA and MC-LR by promoting cytoskeletal rearrangements and inhibiting ER stress of MYH9+ epithelial cell. Mechanistically, hsa_circ_0063865 acted as a modular scaffold to tether eEF1A2(126-177nt of hsa_circ_0063865) and NMIIA (601-658nt of hsa_circ_0063865), thereby promoting NMIIA translation by enhancing the interaction between eEF1A2 and NMIIA, which further promoted cytoskeletal reorganization; Additionally, hsa_circ_0063865 competitively upregulated RCN1 expression by sponging miR-450b-3p, resulting in ER stress inhibition and depolarization of mitochondrial membrane potential via activation of the PERK-eIF2α-ATF4-CHOP axis in MYH9+ epithelial cell.

Conclusion

These findings identify a novel chemical carcinogenic target and elucidate the dual-regulatory mechanism of hsa_circ_0063865 in NAs and MC-LR-induced esophageal carcinogenesis.