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Background <p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death globally, highlighting the urgent need for new molecular drivers and therapeutic targets. This study investigates the role of protein tyrosine phosphatase receptor type H (PTPRH) and its regulation through an epitranscriptomic mechanism in NSCLC.</p> Methods <p>We performed an integrated analysis of datasets from The Cancer Genome Atlas and Gene Expression Omnibus to evaluate PTPRH expression and its prognostic significance. PTPRH levels were further validated in clinical NSCLC specimens and correlated with clinicopathological features. We assessed the functional consequences of PTPRH expression on proliferation, apoptosis, migration, invasion, and angiogenesis using in vitro and in vivo models. The underlying mechanism involving N6-methyladenosine (m6A) modification was explored by examining the roles of the m6A writer RBM15 and the reader IGF2BP2 on PTPRH transcript stability. Gain- and loss-of-function experiments, coupled with rescue studies, were conducted to delineate the functional axis.</p> Results <p>PTPRH was significantly overexpressed in NSCLC tissues, and its elevated expression correlated with poor patient prognosis. Functionally, PTPRH promoted tumor cell proliferation, migration, invasion, and xenograft tumor growth, while simultaneously inhibiting apoptosis and enhancing angiogenesis via the VEGF pathway. Mechanistically, PTPRH expression was post-transcriptionally stabilized by m6A methylation. RBM15 facilitated m6A deposition on PTPRH transcripts, while IGF2BP2 binding to these modified sites enhanced PTPRH mRNA stability. Depletion of RBM15 or IGF2BP2 reduced PTPRH levels and suppressed malignant behaviors, whereas their overexpression produced the opposite effects. The oncogenic functions of PTPRH were confirmed to be dependent on this regulatory axis.</p> Conclusion <p>Our study unveils a novel epigenetic regulatory axis in which RBM15-mediated m6A modification and IGF2BP2-dependent recognition stabilize PTPRH mRNA, thereby promoting NSCLC progression. This work expands the understanding of post-transcriptional regulation in lung cancer and identifies the RBM15/IGF2BP2–PTPRH axis as a potential therapeutic target for NSCLC intervention.</p>

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RBM15/IGF2BP2–PTPRH m6A regulatory axis in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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  • Keyue Qiu,
  • Xiaoxiao Zheng,
  • Hongxiang Li,
  • Jiaheng Zhang,
  • Zijun Xie,
  • Hang Chen,
  • Zeyang Hu,
  • Yiyi Sun,
  • Zhe Chen,
  • Jingtao Tong,
  • Yinyu Mu,
  • Yuanyuan Yao,
  • Wei Chen,
  • Guodong Xu

摘要

Background

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death globally, highlighting the urgent need for new molecular drivers and therapeutic targets. This study investigates the role of protein tyrosine phosphatase receptor type H (PTPRH) and its regulation through an epitranscriptomic mechanism in NSCLC.

Methods

We performed an integrated analysis of datasets from The Cancer Genome Atlas and Gene Expression Omnibus to evaluate PTPRH expression and its prognostic significance. PTPRH levels were further validated in clinical NSCLC specimens and correlated with clinicopathological features. We assessed the functional consequences of PTPRH expression on proliferation, apoptosis, migration, invasion, and angiogenesis using in vitro and in vivo models. The underlying mechanism involving N6-methyladenosine (m6A) modification was explored by examining the roles of the m6A writer RBM15 and the reader IGF2BP2 on PTPRH transcript stability. Gain- and loss-of-function experiments, coupled with rescue studies, were conducted to delineate the functional axis.

Results

PTPRH was significantly overexpressed in NSCLC tissues, and its elevated expression correlated with poor patient prognosis. Functionally, PTPRH promoted tumor cell proliferation, migration, invasion, and xenograft tumor growth, while simultaneously inhibiting apoptosis and enhancing angiogenesis via the VEGF pathway. Mechanistically, PTPRH expression was post-transcriptionally stabilized by m6A methylation. RBM15 facilitated m6A deposition on PTPRH transcripts, while IGF2BP2 binding to these modified sites enhanced PTPRH mRNA stability. Depletion of RBM15 or IGF2BP2 reduced PTPRH levels and suppressed malignant behaviors, whereas their overexpression produced the opposite effects. The oncogenic functions of PTPRH were confirmed to be dependent on this regulatory axis.

Conclusion

Our study unveils a novel epigenetic regulatory axis in which RBM15-mediated m6A modification and IGF2BP2-dependent recognition stabilize PTPRH mRNA, thereby promoting NSCLC progression. This work expands the understanding of post-transcriptional regulation in lung cancer and identifies the RBM15/IGF2BP2–PTPRH axis as a potential therapeutic target for NSCLC intervention.