Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Pang, Xin; Zhou, Zhixia; Yu, Zhuang; Han, Lichun; Lin, Zhijuan; Ao, Xiang; Liu, Chang; He, Yuqi; Ponnusamy, Murugavel; Li, Peifeng; Jx, Wang

doi:10.1080/15476286.2019.1565665

Cited by 27 publications

(20 citation statements)

References 52 publications

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“…Similarly, previous studies also reported that FOXO3a expression levels could be used as a prognostic biomarker for clear cell renal cell carcinoma, cervical carcinoma and colorectal cancer ( 14 , 29 , 42 ). Interestingly, the overexpression of FOXO3a has been associated with the poor prognosis of patients with triple negative breast cancer, glioblastoma and gastric cancer, while downregulated expression levels of FOXO3a were associated with the poor prognosis of patients with glioma and ovarian cancer ( 44 – 45 ). Therefore, these studies suggested that FOXO3a may be a potential biomarker for the diagnosis of nephroblastoma, and may potentially serve as an oncogene or suppressor factor to be investigated in relation to nephroblastoma progression, which requires further investigations.…”

Section: Discussionmentioning

confidence: 99%

FOXO3a inhibits nephroblastoma cell proliferation, migration and invasion, and induces apoptosis through downregulating the Wnt/β‑catenin signaling pathway

Qian

Liu

2021

Mol Med Rep

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Forkhead transcription factor O subfamily 3A (FOXO3a) is an important tumor suppressor gene that is expressed in renal tissue and has been reported to be downregulated in clear cell renal cell carcinoma (CCRCC). Notably, the overexpression of FOXO3a was previously discovered to inhibit the progression of CCRCC. However, the expression levels of FOXO3a in nephroblastoma cell lines remain unknown. The present study aimed to investigate the expression levels of FOXO3a in nephroblastoma cell lines and to determine the mechanism of action of the biological functions of FOXO3a. Western blotting and reverse transcription-quantitative PCR were used to analyze the expression levels of FOXO3a in nephroblastoma cell lines. Subsequently, the effects of the overexpression of FOXO3a and the genetic knockdown of the Wnt/β-catenin signaling protein Axin-2 on the biological functions were determined through Cell Counting Kit-8, cell colony formation assays, scratch and Transwell assay and flow cytometric analysis experiments. The expression levels of FOXO3a were discovered to be downregulated in nephroblastoma cell lines. The overexpression of FOXO3a inhibited the proliferation, invasion and migration of nephroblastoma cells, while inducing apoptosis. Furthermore, the overexpression of FOXO3a downregulated the expression levels of β-catenin and Cyclin-D1 proteins involved in the Wnt/β-catenin signaling pathway. Cell proliferation and the migration and invasion ability of 17–94 cells in shRNA-Axin2-2 group were promoted. Cell apoptosis was predominantly increased by overexpressed FOXO3a, which was reversed by shRNA-Axin2-1. The biological effects of overexpressing FOXO3a on nephroblastoma were reversed after activation of Wnt/β-catenin. In conclusion, the findings of the present study suggested that FOXO3a may inhibit nephroblastoma cell proliferation, migration and invasion, while inducing apoptosis, by downregulating the Wnt/β-catenin signaling pathway. These results may provide a novel method for the early diagnosis and precise treatment of nephroblastoma.

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Section: Discussionmentioning

confidence: 99%

FOXO3a inhibits nephroblastoma cell proliferation, migration and invasion, and induces apoptosis through downregulating the Wnt/β‑catenin signaling pathway

Qian

Liu

2021

Mol Med Rep

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“…In mouse aged kidney, the SIRT1-FOXO3 pathway improved cellular adaption to hypoxia by inducing mitochondrial autophagy 30 . In GC, FOXO3 has been shown to be expressed at low levels and exerts antitumor effects 31,32 . The results of this study demonstrated that deletion of FOXO3a reverses the effects induced by SIRT1 overexpression in GC cells.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Wang

et al. 2020

Cell Death Dis

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Chemotherapy is the standard care for patients with gastric cancer (GC); however, resistance to existing drugs has limited its success. The persistence of cancer stem cells (CSCs) is considered to be responsible for treatment failure. In this study, we demonstrated that SIRT1 expression was significantly downregulated in GC tissues, and that a low SIRT1 expression level indicated a poor prognosis in GC patients. We observed a suppressive role of SIRT1 in chemoresistance of GC both in vitro and in vivo. In addition, we found that SIRT1 eliminated CSC properties of GC cells. Mechanistically, SIRT1 exerted inhibitory activities on chemoresistance and CSC properties through FOXO3 and AMPK. Furthermore, a synergistic effect was revealed between FOXO3 and AMPK. AMPK promoted nuclear translocation of FOXO3 and enhanced its transcriptional activities. In addition, FOXO3 increased the expression level and activation of AMPKα by directly binding to its promoter and activating the transcription of AMPKα. Similar to SIRT1, low expression levels of p-AMPKα and FOXO3a are also related to the poor prognosis of GC patients. Moreover, we revealed a correlation between the expression levels of SIRT1, p-AMPKα, and FOXO3a. These findings indicated the importance of the SIRT1-AMPK/FOXO3 pathway in reversing chemoresistance and CSC properties of GC. Thus, exploring efficient strategies to activate the SIRT1-AMPK/FOXO3 pathway may lead to improving the survival of GC patients.

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“…Through silencing PTEN and tissue inhibitor of matrix metalloproteinases 3 (TIMP3), miR-21-5p increases ADR resistance of gastric cancer cells [61]. It has also been found that miR-633 promotes ADR resistance of gastric cancer by inhibiting expression of Fas-associated death domain (FADD) [62]. In addition, epigenetics controlling mediated by miRNAs has been reported as an important signaling impacting tumorigenesis of gastric cancer.…”

Section: Mirnas and Adr Resistancementioning

confidence: 99%

Noncoding RNAs in gastric cancer: implications for drug resistance

et al. 2020

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Gastric cancer is the fourth most common malignancy and the third leading cause of cancer-related deaths worldwide. Advanced gastric cancer patients can notably benefit from chemotherapy including adriamycin, platinum drugs, 5-fluorouracil, vincristine, and paclitaxel as well as targeted therapy drugs. Nevertheless, primary drug resistance or acquisition drug resistance eventually lead to treatment failure and poor outcomes of the gastric cancer patients. The detailed mechanisms involved in gastric cancer drug resistance have been revealed. Interestingly, different noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are critically involved in gastric cancer development. Multiple lines of evidences demonstrated that ncRNAs play a vital role in gastric cancer resistance to chemotherapy reagents and targeted therapy drugs. In this review, we systematically summarized the emerging role and detailed molecular mechanisms of ncRNAs impact drug resistance of gastric cancer. Additionally, we propose the potential clinical implications of ncRNAs as novel therapeutic targets and prognostic biomarkers for gastric cancer.

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Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Cited by 27 publications

References 52 publications

FOXO3a inhibits nephroblastoma cell proliferation, migration and invasion, and induces apoptosis through downregulating the Wnt/β‑catenin signaling pathway

FOXO3a inhibits nephroblastoma cell proliferation, migration and invasion, and induces apoptosis through downregulating the Wnt/β‑catenin signaling pathway

SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Noncoding RNAs in gastric cancer: implications for drug resistance

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