aGenome-scale activation screen reveals lncRNA HNF1A-AS1 promotes pancreatic cancer metastasis through interacting with U2SURP to increase CD44 alternative splicing.

Jun 16, 2025

Experts: Shan Lei,Zhixue Zhang,Zhirui Zeng,Wenpeng Cao,Yating Sun,Dahuan Li,Jigang Pan,Yingmin Wu,Tuo Zhang,Tengxiang Chen

Pancreatic cancer (PC) has a strong ability to invade and metastasize, which has brought insurmountable obstacles to the treatment of PC. Exploring the molecular mechanism of PC metastasis is still the focus of PC research. The purpose of this study was to explore the molecular mechanism of long noncoding RNA HNF1A-AS1 in promoting PC metastasis, hoping to provide help for the diagnosis and treatment of PC.
CRISPR/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA)-pooled lncRNA libraries were used to screen for the critical lncRNAs regulating PC metastasis. Investigation into HNF1A-AS1’s impact on PC cell migration and invasion were conducted through both loss-of-function and gain-of-function approaches. A range of techniques, including fluorescence in situ hybridization (FISH), mRNA sequencing, bioinformatics analysis, dual-luciferase reporter assays, RNA pull-down assays, ChIP-PCR, and rescue assay to explore the regulatory mechanism of HNF1A-AS1 in PC metastasis.
SNAI2 activates HNF1A-AS1 transcription. HNF1A-AS1 recruits U2SURP (RRM-dependent domain-dependent) through the 1001-1500 nt region (BR3) to form a functional complex (SNAI2-lncRNA HNF1A-AS1-U2SURP) within the nucleus of PC cells, specifically promoting alternative splicing of CD44 pre-mRNA, transforming it from standard isoform CD44s-CD44v (3-10) isoform, thereby promoting PC invasion and metastasis.
This study revealed for the first time that SNAI2 activates the transcription of HNF1A-AS1, and HNF1A-AS1 promote U2SURP to regulate the alternative splicing of CD44 pre-mRNA, causing it to produce a large number of CD44v (3-10) isoforms, thereby promoting the invasion and metastasis of PC.

© 2025. The Author(s), under exclusive licence to Japanese Society of Gastroenterology.

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ABOUT THE EXPERTS

Shan Lei,Zhixue Zhang,Zhirui Zeng,Wenpeng Cao,Yating Sun,Dahuan Li,Jigang Pan,Yingmin Wu,Tuo Zhang,Tengxiang Chen

Shan Lei

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, China.

Zhixue Zhang

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, China.

Zhirui Zeng

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, China.

Wenpeng Cao

Department of Anatomy, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Yating Sun

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, China.

Dahuan Li

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Jigang Pan

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Yingmin Wu

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research On Common Chronic Diseases, Guizhou Medical University, Guiyang, 550009, China.

Tuo Zhang

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China.

Tengxiang Chen

Department of Physiology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, 550009, Guizhou, China. txch@gmc.edu.cn.

Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, Guiyang, 550009, Guizhou, China. txch@gmc.edu.cn.