SOX9/miR-203a axis drives PI3K/AKT signaling to promote esophageal cancer progression

Wang, Lianghai; Zhang, Zhe; Yu, Xiaodan; Li, Qihang; Wang, Qian; Chang, Ana M.; Huang, Xiaoxi; Han, Xiao; Song, Yangguang; Hu, Jianming; Pang, Lijuan; Hou, Jun; Li, Feng

doi:10.1016/j.canlet.2019.10.004

Cited by 72 publications

(51 citation statements)

References 51 publications

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“…A member of the SOX transcription family, SOX9 is elevated in various cancers, including esophageal, 33 lung, 34 and gastric 35 cancers, but its effect on cardiac diseases remains to be elucidated. SOX9 is a key transcription factor involved in the development and pathological changes of the heart valves, and its expression and subcellular localization varied at different stages 36‐38 .…”

Section: Discussionmentioning

confidence: 99%

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Cui¹,

Liu²,

Bo³

et al. 2020

J of Cellular Biochemistry

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Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA-145 (miR-145) and transcription factor sex-determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI-induced fibrosis. Flow cytometry, cell counting kit-8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR-145 expression was measured by quantitative real-time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham-operated group, the expression of miR-145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR-145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR-145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR-145. Overexpression of miR-145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR-145 or suppression of SOX9 inhibited AKT and β-catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR-145, and our findings indicate that miR-145 exerts anti-fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK-3β/β-catenin pathways.

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Section: Discussionmentioning

confidence: 99%

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

Cui¹,

Liu²,

Bo³

et al. 2020

J of Cellular Biochemistry

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“…Aberrant miRNA expression has been reported to play an important role in EC. MiR-203a has been shown to inactivate the PI3K/AKT/mTOR pathway and inhibit EC development ( 31 ), while microRNA-10b induces cisplatin resistance by targeting PPARγ in EC ( 32 ). However, the function and molecular mechanism of miRNA-1324 in EC progression are yet to be deciphered.…”

Section: Discussionmentioning

confidence: 99%

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

et al. 2020

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings. Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo , knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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“…MiR-203a has been shown to inactivate the PI3K/AKT/mTOR pathway and inhibit EC development [31], while microRNA-10b induces cisplatin resistance by targeting PPARγ in EC [32]. However, the function and molecular mechanism of miRNA-1324 in EC progression are yet to be deciphered.…”

Section: Discussionmentioning

confidence: 99%

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

Dong

Huang

Jiang

et al. 2020

Preprint

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings.Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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SOX9/miR-203a axis drives PI3K/AKT signaling to promote esophageal cancer progression

Cited by 72 publications

References 51 publications

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

miR‐145 attenuates cardiac fibrosis through the AKT/GSK‐3β/β‐catenin signaling pathway by directly targeting SOX9 in fibroblasts

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

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