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MiR-708-3p promotes gastric cancer progression through downregulating ETNK1.

ABSTRACT: MicroRNAs (miRNAs) are small, evolutionarily conserved, non-coding RNAs playing a role in the proliferation, metastasis, apoptosis, chemo-sensitivity, and chemo-resistance of gastric cancer, as well as the stemness of gastric cancer stem cells. miR-708-3p induces gastric cancer cell chemo-resistance, but its actual role in gastric cancer progression remains unclear. This paper shows that miR-708-3p is upregulated in gastric cancer samples and that a high miR-708-3p expression in gastric cancer patients is associated with poor overall survival. Our functional study results indicate that miR-708-3p overexpression promotes gastric cancer cell proliferation and migration, inhibits cell apoptosis, and facilitates the transition from the G0/G1 to the G2/M phase. Furthermore, reducing miR-708-3p levels yielded opposite effects. Next, our in vivo experiments revealed that miR-708-3p advanced gastric cancer cell growth in nude mice. The underlying mechanism was the regulation of ethanolamine kinase 1 (ETNK1) expression by miR-708-3p, which bound to the 3'UTR of the ETNK1 gene in gastric cancer cells. Finally, the recovery assay results showed that ETNK1 overexpression could slow miR-708-3p-induced gastric cancer progression. In conclusion, we identified a new miR-708-3p/ETNK1 pathway involved in gastric cancer progression. These results may offer new targets for gastric cancer therapy and markers for gastric cancer prognosis.

SUBMITTER: Shang J

PROVIDER: S-EPMC10558739 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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miR-708-3p promotes gastric cancer progression through downregulating ETNK1.

Shang Jincai J Wang Qingdong Q Wang Jingren J Xu Bo B Liu Shuang S

Heliyon 20230828 9

MicroRNAs (miRNAs) are small, evolutionarily conserved, non-coding RNAs playing a role in the proliferation, metastasis, apoptosis, chemo-sensitivity, and chemo-resistance of gastric cancer, as well as the stemness of gastric cancer stem cells. miR-708-3p induces gastric cancer cell chemo-resistance, but its actual role in gastric cancer progression remains unclear. This paper shows that miR-708-3p is upregulated in gastric cancer samples and that a high miR-708-3p expression in gastric cancer p ...[more]

PMID: 37809692

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Project description:BackgroundMounting evidences indicate that circular RNAs (circRNAs) play vital roles in the development and progression of various cancers. However, the detail functions and underlying mechanisms of circRNAs in gastric cancer remain largely unknown.MethodsThe expression profile of metastasis-related circRNAs was screened by RNA-seq analysis. qRT-PCR was used to determine the level and prognostic values of circNHSL1 in gastric cancer tissues. In vitro cell wound healing and transwell (migration and invasion) and in vivo tumorigenesis and metastasis assays were performed to evaluate the functions of circNHSL1. Luciferase reporter, RNA immunoprecipitation (RIP) and rescued assays were employed to confirm the interactions between circNHSL1, miR-1306-3p and SIX1. It's widely accepted that as a mesenchymal marker, Vimentin promotes invasion and metastasis in various cancers. Luciferase reporter assay was used to determine the regulation of SIX1 on Vimentin. In addition, In situ hybridization (ISH) was performed to detect the level and prognostic values of miR-1306-3p.ResultsWe found that the level of circNHSL1 was significantly up-regulated in gastric cancer, and positively correlated with clinicopathological features and poor prognosis of patients with gastric cancer. Functionally, circNHSL1 promoted cell mobility and invasion, as well as in vivo tumorgenesis and metastasis. Mechanistically, circNHSL1 acted as a miR-1306-3p sponge to relieve the repressive effect of miR-1306-3p on its target SIX1. Moreover, SIX1 enhanced Vimentin expression in the transcriptional level through directly binding to the promoter domain of Vimentin, thereby promoting cell migration and invasion. In addition, miR-1306-3p was down-regulated and negatively correlated with pathological features and poor prognosis in gastric cancer.ConclusionsCircNHSL1 promotes gastric cancer progression through miR-1306-3p/SIX1/Vimentin axis, and may serve as a novel diagnostic marker and target for treatment of gastric cancer patients.

Project description:BackgroundCircular RNAs (circRNAs) regulate multiple malignant behaviors of various types of cancer. The role of circDNMT1, a newly identified circRNA, remains unknown in gastric cancer (GC). This study aimed to elucidate the underlying mechanisms of circDNMT1 in regulating GC progression.MethodsmicroRNA (miRNA) and circRNA expression was detected by quantitative real-time PCR. Western blotting was performed to measure hypoxia inducible factor-1 alpha (HIF-1α) protein expression. Sanger sequencing, gel electrophoresis and fluorescence in situ hybridization were performed to identify the presence of circDNMT1. The clinicopathological features and overall survival of patients were analyzed based on circDNMT1 expression. The proliferation, migration and invasion of GC cells were determined by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, wound healing and transwell assays. Glycolysis of GC cells was detected based on the levels of glucose uptake, the lactate acid, ATP and pyruvic acid production and the extracellular acidification and oxygen consumption rates. The binding sites between miR-576-3p and circDNMT1 or HIF-1α were predicted by online bioinformatic tools and were validated using RNA pull-down and luciferase reporter assays. Xenograft models were established to determine the effects of the circDNMT1/miR-576-3p/HIF-1α axis on GC growth and metastasis in vivo.ResultscircDNMT1 was successfully identified and shown to be overexpressed in GC tissues and cell lines. The expression levels of circDNMT1 were correlated with pathological T stage, pathological TNM stage and shorter survival time of GC patients. circDNMT1 knockdown inhibited the proliferation, migration, invasion and glycolysis of GC cells. circDNMT1 functioned as an oncogenic factor by sponging miR-576-3p. HIF-1α was negatively regulated by miR-576-3p via binding its mRNA 3' untranslated region. circDNMT1 promoted malignant behaviors and metabolic reprogramming of GC by targeting the miR-576-3p/HIF-1α axis both in vitro and in vivo.ConclusionThese findings demonstrated that circDNMT1 knockdown inhibited GC proliferation, migration, invasion and glycolysis through sponging miR-576-3p/HIF-1α axis. circDNMT1 may be a novel target for GC treatment.

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MiR-708-3p promotes gastric cancer progression through downregulating ETNK1.

Publications

miR-708-3p promotes gastric cancer progression through downregulating ETNK1.

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