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<p>Sonic Hedgehog signaling is aberrantly activated in non-small cell lung cancer (NSCLC). However, the regulatory molecules of Sonic Hedgehog signaling during NSCLC development are still largely unknown. Here, we demonstrated that HHIP Like 2 (HHIPL2) is a crucial Sonic Hedgehog signaling regulator, accelerating NSCLC progression via positively governing Sonic Hedgehog signaling. Clinically, HHIPL2 is highly expressed in NSCLC and indicates a poor prognosis. Consistently, via depletion or gain of HHIPL2 in vivo and in vitro, we identified its oncogenic role in NSCLC proliferation and metastasis. Mechanistically, HHIPL2 interacted with the RNA-binding protein HNRNPC to alter its nucleo-cytoplasmic translocation. HHIPL2-regulated HNRNPC accumulation in the cytoplasm promoted the mRNA stability of HNF1A, a transcription factor for SHH, which subsequently enhanced the Sonic Hedgehog signaling activity to facilitate NSCLC progression. Furthermore, we discovered that triptolide (TPL), an HNF1A inhibitor, impeded HHIPL2-mediated Sonic Hedgehog signaling activation and NSCLC malignancy. Therefore, our findings not only uncover a previously unrecognized role for HHIPL2 in regulating the Sonic Hedgehog signaling pathway but also highlight a novel HHIPL2/HNRNPC/HNF1A axis as an attractive target for NSCLC therapy.</p><p></p>

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HHIPL2 positively governs Hedgehog signaling to accelerate non-small cell lung cancer progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Ning Mu,
  • Fanrong Liu,
  • Xiangqing Song,
  • Biao Wang,
  • Yilin Zhu,
  • Lingbing Li,
  • Lingxiao Yang,
  • Huacong Sui,
  • Jinfu Wang,
  • Fengyuan Gao,
  • Yongjia Zhou,
  • Yanfeng Lv,
  • Zhongxian Tian,
  • Peichao Li,
  • Xiaogang Zhao

摘要

Sonic Hedgehog signaling is aberrantly activated in non-small cell lung cancer (NSCLC). However, the regulatory molecules of Sonic Hedgehog signaling during NSCLC development are still largely unknown. Here, we demonstrated that HHIP Like 2 (HHIPL2) is a crucial Sonic Hedgehog signaling regulator, accelerating NSCLC progression via positively governing Sonic Hedgehog signaling. Clinically, HHIPL2 is highly expressed in NSCLC and indicates a poor prognosis. Consistently, via depletion or gain of HHIPL2 in vivo and in vitro, we identified its oncogenic role in NSCLC proliferation and metastasis. Mechanistically, HHIPL2 interacted with the RNA-binding protein HNRNPC to alter its nucleo-cytoplasmic translocation. HHIPL2-regulated HNRNPC accumulation in the cytoplasm promoted the mRNA stability of HNF1A, a transcription factor for SHH, which subsequently enhanced the Sonic Hedgehog signaling activity to facilitate NSCLC progression. Furthermore, we discovered that triptolide (TPL), an HNF1A inhibitor, impeded HHIPL2-mediated Sonic Hedgehog signaling activation and NSCLC malignancy. Therefore, our findings not only uncover a previously unrecognized role for HHIPL2 in regulating the Sonic Hedgehog signaling pathway but also highlight a novel HHIPL2/HNRNPC/HNF1A axis as an attractive target for NSCLC therapy.