Abstract
Bile acids (BAs), well-defined signaling molecules with diverse metabolic functions, play important roles in cellular processes associated with many cancers. As one of the most common BAs, deoxycholic acid (DCA) is originally synthesized in the liver, stored in the gallbladder, and processed in the gut. DCA plays crucial roles in various tumors; however, functions and molecular mechanisms of DCA in gallbladder cancer (GBC) still remain poorly characterized. Here, we analyzed human GBC samples and found that DCA was significantly downregulated in GBC, and reduced levels of DCA was associated with poor clinical outcome in patients with GBC. DCA treatment impeded tumor progression by halting cell proliferation. DCA decreased miR-92b-3p expression in an m6A-dependent posttranscriptional modification manner by facilitating dissociation of METTL3 from METTL3–METTL14–WTAP complex, which increased the protein level of the phosphatase and tensin homolog, a newly identified target of miR-92b-3p, and subsequently inactivated the PI3K/AKT signaling pathway. Our findings revealed that DCA might function as a tumor suppressive factor in GBC at least by interfering with miR-92b-3p maturation, and suggested that DCA treatment could provide a new therapeutic strategy for GBC.
Highlights
Gallbladder cancer (GBC) represents almost all common malignancies of the biliary tract, with a median survival rate of 6 months [1]
Our results showed that deoxycholic acid (DCA) levels in serum were downregulated in patients with GBC, which could contribute to tumor formation by increasing m6A modification level of pri-miR-92b, which targeted phosphatase and tensin homolog (PTEN) gene and promoted PI3K/AKT pathway signaling
Contradictory findings suggest that Bile acids (BAs) exert both protective and cytotoxic effects on cells, further investigation revealed that the impact of BAs on cell fate is determined by cell types as well as BA subsets, in which conjugate BAs usually promote cell proliferation, whereas free BAs inhibit cell survival [17,18,19,20]
Summary
Gallbladder cancer (GBC) represents almost all common malignancies of the biliary tract, with a median survival rate of 6 months [1]. Relatively rare, it is the sixth most common gastrointestinal cancer worldwide [2]. Complete surgical resection is the only potentially curative therapy for GBC; fewer than 10% of patients are considered surgical candidates owing to the advanced stage of disease in the majority, resulting in a poor clinical outcome [3]. The chemotherapy with cisplatin plus gemcitabine has been proposed as an appropriate choice for patients with advanced GBC [4, 5]. Lacks of a biomarker for early diagnosis and effective chemotherapy with a defined target for GBC are still a major hindrance for treatment, identifying novel targets both for diagnosis and treatment need to be urgently resolved
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