Circ\u03b2-catenin promotes tumor growth and Warburg effect of gallbladder cancer by regulating STMN1 expression

Shouhua Wang,Huanjun Tong,Weibin Shi,Fei Ma,Tingting Su,Jun Ding,Di Zhou,Zhiwei Quan,Yuan Hao

doi:10.1038/s41420-021-00626-6

Abstract

Gallbladder cancer (GBC) is the most malignant cancer of the biliary tract cancer and presents poor prognosis. CircRNAs have been identified as critical regulators of multiple stages in tumor progression. In the study, we first demonstrated that circular RNA circβ-catenin expression was upregulated in GBC tissues when compared to adjacent normal tissues and associated with advanced clinical stage and poor prognosis in GBC patients. Silencing of circβ-catenin obviously suppressed GBC cell proliferation and cell cycle progression in vitro, but circβ-catenin overexpression had the opposite effects. In vivo, silencing of circβ-catenin inhibited tumor growth. Furthermore, we also found that circβ-catenin promoted GBC cell lactate production, pyruvate production, ATP quantity, and extracellular acidification rate (ECAR), which suggested that circβ-catenin regulated Warburg effect in GBC. Mechanistic analysis further highlighted that circβ-catenin promoted Stathmin 1 (STMN1) expression through sponging miR-223 in GBC progression. In addition, knockdown of STMN1 inhibited cell growth and Warburg effect in GBC. In summary, our findings indicated that circβ-catenin/miR-223/STMN1 axis could regulate cell growth and Warburg effect in GBC. Targeting circβ-catenin might be a potential therapeutic strategy for GBC.

Highlights

Gallbladder cancer (GBC) is the fifth most common cancer among gastrointestinal cancers and the most common cancer of the biliary tract worldwide [1]
E RNase R was used to pretreat the RNAs and we found that the circular form of circβ-catenin was resistant to RNase R in four GBC cell lines compared with control group
RNase R was used to pretreat the RNAs and we found that the circular form of circβ-catenin was resistant to RNase R in four GBC cell lines compared with control group (Fig. 1E)

Summary

Introduction

Gallbladder cancer (GBC) is the fifth most common cancer among gastrointestinal cancers and the most common cancer of the biliary tract worldwide [1]. Due to the absence of specific symptoms and effective treatment strategies at advanced stage for GBC patients, less than 50% of preoperatively known gallbladder cancer patients are candidates for curative resection [2]. The exact molecular alteration underlying gallbladder cancer pathogenesis remains largely unknown and the prognostic markers or therapeutic strategies are urgently needed. CircRNAs garnered more attention and are found to be associated with tumorigenesis as well as their potential as diagnostic and prognostic biomarkers for some human cancers [7, 8]. Circular RNA_LARP4 (circLARP4) is downregulated in gastric cancer and sponges to miR-424 by circRNA expression profile and bioinformatic analysis and inhibits biological behaviors of gastric cancer by affecting LATS1 expression [10]. Researchers showed that a circRNA generated from the oncogene ERBB2, named as circERBB2 promotes gallbladder cancer progression by regulating PA2G4-dependent rDNA transcription [12]

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Conclusion