Zhang XL, Zhu JY, Yang JL, Du LL, Tian KW, Zhang JG, Li XP. Recent advances on regulatory roles of HuD and promoter hypermethylation for miR-204 in lung cancer development. World J Clin Oncol 2026; 17(9): 124498 [DOI: 10.5306/wjco.124498]
Corresponding Author of This Article
Xiao-Ping Li, Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, No. 8 Shuren Street, Hangzhou 310015, Zhejiang Province, China. li-xp@zjsru.edu.cn
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Immunology
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review-article
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Zhang XL, Zhu JY, Yang JL, Du LL, Tian KW, Zhang JG, Li XP. Recent advances on regulatory roles of HuD and promoter hypermethylation for miR-204 in lung cancer development. World J Clin Oncol 2026; 17(9): 124498 [DOI: 10.5306/wjco.124498]
World J Clin Oncol. Sep 24, 2026; 17(9): 124498 Published online Sep 24, 2026. doi: 10.5306/wjco.124498
Recent advances on regulatory roles of HuD and promoter hypermethylation for miR-204 in lung cancer development
Xin-Ling Zhang, Jia-Yi Zhu, Jian-Lan Yang, Lai-Ling Du, Ke-Wei Tian, Jian-Guo Zhang, Xiao-Ping Li
Xin-Ling Zhang, Jia-Yi Zhu, Lai-Ling Du, Ke-Wei Tian, Xiao-Ping Li, Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou 310015, Zhejiang Province, China
Jian-Lan Yang, Gongshu District People’s Hospital of Integrated Traditional Chinese and Western Medicine, Hangzhou 310004, Zhejiang Province, China
Jian-Guo Zhang, Hangzhou Huijian Medical Technology Co., Ltd, Hangzhou 311113, Zhejiang Province, China
Co-first authors: Xin-Ling Zhang and Jia-Yi Zhu.
Author contributions: Zhang XL and Zhu JY constructed the framework construction, collected literature, drafted the original manuscript and performed writing review and editing, qualified as the co-first authors of the paper; Yang JL, Du LL, Tian KW and Zhang JG performed writing review and editing; Li XP supervised the study, provided research resources; all authors have accepted responsibility for the entire content of this manuscript and approved its submission.
AI contribution statement: AI tool (ChatGPT) was used solely for linguistic refinement. No AI tool was involved in the interpretation of results or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by General Scientific Research Project of Zhejiang Provincial Department of Education, No. Y202147513.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Xiao-Ping Li, Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, No. 8 Shuren Street, Hangzhou 310015, Zhejiang Province, China. li-xp@zjsru.edu.cn
Received: June 23, 2026 Revised: August 10, 2026 Accepted: September 21, 2026 Published online: September 24, 2026 Processing time: 98 Days and 23.4 Hours
Abstract
Lung cancer, responsible for the highest number of cancer-related deaths globally, comprises small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), two subtypes with fundamentally different molecular mechanisms and disease trajectories. The tumor-suppressive microRNA miR-204 is frequently inactivated in lung cancer and plays a central role in driving progression and metastasis. Recent work has uncovered striking differences in how miR-204 is downregulated in each subtype. In SCLC, the RNA-binding protein HuD stabilizes oncogenic long non-coding RNAs (lncRNAs) and PFN2 mRNA, leading to reduced miR-204-5p levels and increased cell migration. By contrast, in NSCLC, epigenetic silencing via miR-204 promoter hypermethylation decreases its expression, derepressing NUAK1, activating mTOR signaling, and promoting tumor progression. Despite operating through distinct pathways, both mechanisms converge on miR-204 loss to foster malignancy. This minireview summarizes these recent insights into the HuD-lncRNA axis and epigenetic regulation of miR-204, evaluates their clinical implications, and discusses emerging multimodal approaches that target the miR-204 network for more effective precision therapy in lung cancer.
Core Tip: miR-204 is a pivotal tumor suppressor in lung cancer, with its inactivation driven by distinct mechanisms across subtypes: In small cell lung cancer, the RNA-binding protein HuD stabilizes oncogenic long non-coding RNAs LYPLAL1-DT and PFN2 mRNA, sequestering miR-204-5p to derepress PFN2 and promote cytoskeletal remodeling and metastasis via a self-amplifying positive feedback loop. In non-small cell lung cancer, promoter hypermethylation mediated by DNA methyltransferase directly silences miR-204 transcription, derepressing NUAK1 to activate mTOR signaling and drive cancer progression. Though operating through discrete upstream pathways and targeting different downstream effectors, the both pathways converge on loss of miR-204 function to foster malignancy. This dual-track regulatory network may provide a basis for subtype-specific molecular typing, prognostic prediction, and targeted intervention strategies, offering new insights for precision therapy of lung cancer.
