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Background <p>Circular RNAs (circRNAs) play critical roles in tumorigenesis. However, their function in cisplatin (CDDP) resistance of non-small cell lung cancer (NSCLC) remains incompletely understood. We aimed to investigate the expression pattern of hsa_circ_0135681 in NSCLC and its role in regulating cisplatin resistance.</p> Method <p>RNA sequencing was performed on serum samples to identify differentially expressed circRNAs (DEcircRNAs) using thresholds of |log2FC| &gt;1 and <i>p</i> &lt; 0.05. We validated candidate DEcircRNAs via quantitative real-time PCR (qRT-PCR) in NSCLC tissues. We conducted functional assays, including CCK-8 proliferation, wound healing assay, and flow cytometry apoptosis analysis. Finally, nude mouse xenograft models were used to investigate the role of circRNA in <i>vivo</i>. In mechanistic investigations, lactate and glucose detection kits were used, with subsequent validation conducted via Western blot (WB) and qRT-PCR.</p> Results <p>A total of 411 DEcircRNAs were identified in serum samples, and the 9 selected candidate DEcircRNAs were further validated in NSCLC tissues. Among these, hsa_circ_0135681 was significantly downregulated in NSCLC tissues compared to adjacent non-cancerous tissues. Overexpression of hsa_circ_0135681 could inhibit the proliferation and migration of A549/DDP cells, induce apoptosis in <i>vitro</i>, and similarly suppress tumorigenesis in <i>vivo</i>. Mechanistically, hsa_circ_0135681 overexpression reduced glycolytic activity and reversed EMT in A549/DDP cells. Additionally, bioinformatics analysis predicted two potential regulatory axes: hsa_circ_0135681/hsa-miR-4299/RNF180 and hsa_circ_0135681/hsa-miR-4299/SOCS5.</p> Conclusion <p>Collectively, hsa_circ_0135681 is a tumor-suppressive circRNA that modulates glycolysis and EMT. These findings may provide a potential therapeutic target for cisplatin-resistant NSCLC.</p>

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hsa_circ_0135681 functions as a novel tumor-suppressive circular RNA regulating Glycolysis and EMT to attenuate cisplatin resistance in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Xiaoyan Song,
  • Huihui Li,
  • Yan Zhu,
  • Guohao Wei,
  • Xiaoqing Li,
  • Hongxuan Wei,
  • Huihui Zhao,
  • Chuandong Zhu,
  • Fangfang Chen

摘要

Background

Circular RNAs (circRNAs) play critical roles in tumorigenesis. However, their function in cisplatin (CDDP) resistance of non-small cell lung cancer (NSCLC) remains incompletely understood. We aimed to investigate the expression pattern of hsa_circ_0135681 in NSCLC and its role in regulating cisplatin resistance.

Method

RNA sequencing was performed on serum samples to identify differentially expressed circRNAs (DEcircRNAs) using thresholds of |log2FC| >1 and p < 0.05. We validated candidate DEcircRNAs via quantitative real-time PCR (qRT-PCR) in NSCLC tissues. We conducted functional assays, including CCK-8 proliferation, wound healing assay, and flow cytometry apoptosis analysis. Finally, nude mouse xenograft models were used to investigate the role of circRNA in vivo. In mechanistic investigations, lactate and glucose detection kits were used, with subsequent validation conducted via Western blot (WB) and qRT-PCR.

Results

A total of 411 DEcircRNAs were identified in serum samples, and the 9 selected candidate DEcircRNAs were further validated in NSCLC tissues. Among these, hsa_circ_0135681 was significantly downregulated in NSCLC tissues compared to adjacent non-cancerous tissues. Overexpression of hsa_circ_0135681 could inhibit the proliferation and migration of A549/DDP cells, induce apoptosis in vitro, and similarly suppress tumorigenesis in vivo. Mechanistically, hsa_circ_0135681 overexpression reduced glycolytic activity and reversed EMT in A549/DDP cells. Additionally, bioinformatics analysis predicted two potential regulatory axes: hsa_circ_0135681/hsa-miR-4299/RNF180 and hsa_circ_0135681/hsa-miR-4299/SOCS5.

Conclusion

Collectively, hsa_circ_0135681 is a tumor-suppressive circRNA that modulates glycolysis and EMT. These findings may provide a potential therapeutic target for cisplatin-resistant NSCLC.