HHIPL2 positively governs Hedgehog signaling to accelerate non-small cell lung cancer progression via enhancing HNRNPC-mediated HNF1A mRNA stabilization PMID: 41413056

ADC Targets in Oncology

2026-04-10

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

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.

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.