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

Shao, Jia; Xu, Linlin; Chen, Limin; Lu, Quqin; Xie, Xinsheng; Shi, Wei; Xiong, Huanting; Shi, Chao; Huang, Xuan; Mei, Jinhong; Rao, Hai; Lu, Hua; Lü, Nonghua; Luo, Shuhong

doi:10.1158/0008-5472.can-16-2461

Cited by 35 publications

(51 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our results, recent studies have uncovered that overexpression of ARL13B and ARL4C is correlated strongly with the poor prognosis of GC patients (23,30). ARL13B may worsen the survival and stimulate GC cell proliferation and migration both in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: As small GTP-binding proteins, ARL family members (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive.Methods: The expression status, interactive relations, potential pathways and genetic variations of ARLs are analyzed by bioinformatics tools. Machine learning models and enrichment analysis are performed by R platform. The biological functions of ARL4C are demonstrated by in vitro and in vivo experiments. The nomogram is further constructed to validate the prognostic value of ARL4C for GC patients.Results: ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant diagnostic and prognostic indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably reverses the epithelial-mesenchymal transition (EMT) and inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that TGF-β1 is highly correlated with ARL4C, while ARL4C-related genes are significantly enriched in the TGF-β1 signaling. Correspondingly, we demonstrate that TGF-β1 treatment dramatically increases ARL4C expression, and ARL4C knockdown reverses TGF-β1-induced EMT possibly by inhibiting the expression of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients both in Kaplan-Meier analysis and nomogram model.Conclusion: Our work is of significance for comprehensively understanding the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.

show abstract

Section: Discussionsupporting

confidence: 92%

“…ARL13B has been previously reported to play a critical role in promoting proliferation, migration and invasion of GC cells and is associated with poor prognosis of GC patients (23). However, the biological functions of ARL4C in gastric tumorigenesis remain unclear.…”

Section: The Diagnostic and Prognostic Values Of Arls For Gcmentioning

confidence: 99%

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Xie¹,

Bai²,

Lu³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…increased SMO accumulation) in cells with a loss‐of‐function mutation in Arl13b . However, in cancer cells, Arl13b promotes the ciliary localisation of SMO, although this difference may be explained by the transformed state of these cells . One scenario to explain our observations is that Rab35 principally targets Arl13b, possibly as a direct effector or a more distant upstream regulator.…”

Section: Discussionmentioning

confidence: 75%

Rab35 controls cilium length, function and membrane composition

et al. 2019

View full text Add to dashboard Cite

Rab and Arl guanine nucleotide‐binding (G) proteins regulate trafficking pathways essential for the formation, function and composition of primary cilia, which are sensory devices associated with Sonic hedgehog (Shh) signalling and ciliopathies. Here, using mammalian cells and zebrafish, we uncover ciliary functions for Rab35, a multitasking G protein with endocytic recycling, actin remodelling and cytokinesis roles. Rab35 loss via siRNAs, morpholinos or knockout reduces cilium length in mammalian cells and the zebrafish left‐right organiser (Kupffer's vesicle) and causes motile cilia‐associated left‐right asymmetry defects. Consistent with these observations, GFP‐Rab35 localises to cilia, as do GEF (DENND1B) and GAP (TBC1D10A) Rab35 regulators, which also regulate ciliary length and Rab35 ciliary localisation. Mammalian Rab35 also controls the ciliary membrane levels of Shh signalling regulators, promoting ciliary targeting of Smoothened, limiting ciliary accumulation of Arl13b and the inositol polyphosphate 5‐phosphatase (INPP5E). Rab35 additionally regulates ciliary PI(4,5)P2 levels and interacts with Arl13b. Together, our findings demonstrate roles for Rab35 in regulating cilium length, function and membrane composition and implicate Rab35 in pathways controlling the ciliary levels of Shh signal regulators.

show abstract

“…However, the heart rate (reported here as the RR interval) was not different amongst the three groups (Table 3). Figure 3D illustrates that AF was induced in 10 out of 17 Figure 3D). Despite the lack of statistical significance, the propensity to develop AF with or without feeding a high-Hcy diet was higher in groups that underwent TAC (HH and NH groups) than in the SH group ( Figure 3D).…”

Section: Patients With Af Are More Often Diagnosed With Severe Cardmentioning

confidence: 98%

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Han

Tang

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

High plasma levels of homocysteine (Hcy) are regarded as a risk factor for atrial fibrillation (AF), which is closely associated with the pathological consequence of atrial fibrosis and can lead to heart failure with a high mortality rate; here, we show that atrial fibrosis is mediated by the relationship between canonical transient receptor potential 3 (TRPC3) channels and sirtuin type 1 (SIRT1) under the stimulation of Hcy. The left atrial appendage was obtained from patients with either sinus rhythm (SR) or AF and used to evaluate the relationship between the concentration of Hcy and a potential mechanism of cardiac fibrosis mediated by TRPC3 and SIRT1. We next performed transverse aortic constriction (TAC) in mouse to investigate the relationship. The mechanisms underlying atrial fibrosis involving TRPC3 and SIRT1 proteins were explored by co‐IP, BLI and lentivirus transfection experiments. qPCR and WB were performed to analyse gene and protein expression, respectively. The higher level of atrial fibrosis was observed in the HH mouse group with a high Hcy diet. Such results suggest that AF patients may be more susceptible to atrial fibrosis and possess a high probability of progressing to hyperhomocysteinemia. Moreover, our findings are consistent with the hypothesis that TRPC3 channel up‐regulation leads to abnormal accumulation of collagen, with the down‐regulation of SIRT1 as an aetiological factor of high Hcy, which in turn predisposes to atrial fibrosis and strongly enhances the possibility of AF.

show abstract

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

Cited by 35 publications

References 48 publications

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

ARL4C is A Key Driver of Gastric Cancer: An Integrative Analysis of ARL Family Members

Rab35 controls cilium length, function and membrane composition

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

Contact Info

Product

Resources

About