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Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.

ABSTRACT: Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking, and localization, which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration, and invasion in vitro and in vivo In clinical specimens of gastric cancer, Arl13b expression correlated strongly with tumor size and depth of invasion; patients with high levels of Arl13b had a poor prognosis. Our results show how Arl13b participates in Hh pathway activation in gastric cancer. Cancer Res; 77(15); 4000-13. ©2017 AACR.

SUBMITTER: Shao J

PROVIDER: S-EPMC5540784 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.

Shao Jia J Xu Linlin L Chen Limin L Lu Quqin Q Xie Xinsheng X Shi Wei W Xiong Huanting H Shi Chao C Huang Xuan X Mei Jinhong J Rao Hai H Lu Hua H Lu Nonghua N Luo Shiwen S

Cancer research 20170613 15

Inhibitors of the Hedgehog (Hh) pathway transducer Smoothened (Smo) have been approved for cancer treatment, but Smo mutations often lead to tumor resistance and it remains unclear how Smo is regulated. In this study, we identified the small GTPase Arl13b as a novel partner and regulator of Smo. Arl13b regulated Smo stability, trafficking, and localization, which are each crucial for Hh signaling. In gastric cancer cells, Arl13b stimulated proliferation, migration, and invasion <i>in vitro</i> a ...[more]

PMID: 28611043

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Project description:BACKGROUND:Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer. METHODS:A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway. RESULTS:Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-?B, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer. CONCLUSIONS:The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.

Dataset Information

Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.

Publications

Arl13b Promotes Gastric Tumorigenesis by Regulating Smo Trafficking and Activation of the Hedgehog Signaling Pathway.

Similar Datasets

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