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

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

  • Cell Death Dis. 2025 Dec 18. doi: 10.1038/s41419-025-08331-3.
Ning Mu # 1 2 3,  Fanrong Liu # 1,  Xiangqing Song # 1,  Biao Wang 1,  Yilin Zhu 1,  Lingbing Li 1,  Lingxiao Yang 1,  Huacong Sui 1,  Jinfu Wang 1,  Fengyuan Gao 1,  Yongjia Zhou 1,  Yanfeng Lv 4,  Zhongxian Tian 1 2 3,  Peichao Li 5 6 7,  Xiaogang Zhao 8 9 10
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 2 Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China.
  • 3 Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China.
  • 4 Department of Colorectal and Anal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
  • 5 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 6 Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China. [email protected].
  • 7 Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China. [email protected].
  • 8 Department of Thoracic Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected].
  • 9 Key Laboratory of Precision Diagnosis and Treatment of Lung Tumors in Shandong Provincial Medicine and Health, Shandong University, Jinan, China. [email protected].
  • 10 Key Laboratory of Basic Research and Clinical Transformation of Thoracic Tumors in Shandong Provincial Colleges and Universities, Shandong University, Jinan, China. [email protected].
  • # Contributed equally.
PMID: 41413056 DOI: 10.1038/s41419-025-08331-3
Abstract

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.Schematic diagram (created by Figdraw.com) showing that HHIPL2 positively governs Hedgehog signaling to accelerate NSCLC progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization.

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