Circular RNA ANAPC7 Inhibits Tumor Growth and Muscle Wasting via PHLPP2–AKT–TGF-β Signaling Axis in Pancreatic Cancer

• DOI: 10.1053/j.gastro.2022.02.017
• Publication Date: 2022-02-14T16:02:20Z
• Authors: Xiuhui Shi; Jingxuan Yang; Mingyang Liu; Yuqing Zhang; Zhijun Zhou; Wenyi Luo; Kar-Ming Fung; Chao Xu; Michael S. Bronze; Courtney W. Houchen; Min Li
• Keywords: 0303 health sciences; Cachexia; Muscles; RNA, Circular; Article; 3. Good health; Pancreatic Neoplasms; Mice; MicroRNAs; 03 medical and health sciences; Transforming Growth Factor beta; Cell Line, Tumor; Phosphoprotein Phosphatases; Animals; Humans; Cyclin D1; Proto-Oncogene Proteins c-akt; Cell Proliferation

Background & AimsPancreatic cancer has the highest prevalence of cancer-associated cachexia among all cancers. ZIP4 promotes pancreatic progression by regulating oncogenic miR-373, and perturbation circular RNAs (circRNAs) is associated with aggressiveness. This study aimed to identify circRNAs involved in ZIP4/miR-373–driven growth decipher underlying mechanism.MethodsDifferentially expressed potential targets microRNA were identified through silico analysis. The RNA interactions determined means biotinylated pulldown, immunoprecipitation, luciferase reporter assays. function circRNA ZIP4–miR-373 signaling axis examined human cells, 3-dimensional spheroids organoids, mouse models, clinical specimens. Mouse skeletal muscles analyzed histology.ResultsWe circANAPC7 as a sponge for which inhibited tumor muscle wasting vitro vivo. Mechanistic studies showed that PHLPP2 downstream target ZIP4/miR-373. CircANAPC7 functions PHLPP2-mediated dephosphorylation AKT, thus suppressing cell proliferation down-regulating cyclin D1 inhibiting via decreasing secretion transforming factor–β STAT5. We further demonstrated induced CREB, zinc-dependent transcription factor activated ZIP4, thereby forming CREB–miR-373–PHLPP2 feed-forward loop regulate cachexia.ConclusionThis novel suppressor, axis, leading AKT dephosphorylation, down-regulation suppress cancer. Pancreatic mechanism. Differentially histology. cachexia.