RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma

Liu, Tianze; Li, Wenbin; Lü, Wenjing; Chen, Miao; Luo, Meihua; Zhang, Changlin; Li, Yixin; Qin, Ge; Shi, Dingbo; Xiao, Binyi; Qiu, Huijuan; Yu, Wei; Kang, Lan; Kang, Tiebang; Huang, Wenlin; Yu, Xiaofeng; Wu, Xiaojun; Deng, Wu

doi:10.7150/thno.19506

Cited by 32 publications

(35 citation statements)

References 51 publications

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“…One study suggested that RBFOX3 might be a transcriptional regulator as it could bind to DNA [16]. Our previous study found that RBFOX3 promoted HCC growth and progression by activating the hTERT signaling [17]. Another study showed that RBFOX3 bound directly to pri-miRNAs and regulated the recruitment of the microprocessor complex to pri-miRNAs [18], which suggested that RBFOX3 possessed a novel function for controlling the biogenesis of a subset of microRNAs.…”

Section: Introductionmentioning

confidence: 99%

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

Liu¹,

Wu²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

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Section: Introductionmentioning

confidence: 99%

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

Liu¹,

Wu²,

Li³

et al. 2018

Cell Physiol Biochem

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“…As the catalytic subunit of telomerase, HTERT plays a decisive role in cell unlimited replication [29][30][31] . Recent findings have implicated HTERT in various human diseases, including cancer [17,30,32] .…”

Section: Discussionmentioning

confidence: 99%

“…Next, we investigated whether RBFOX3 bound to the HTERT promoter interacts with other transcription factors. Previous studies have found that HTERT promoterbinding proteins include KLF4 [21] , RFPL3 [22] , CPSF4 [23] and AP-2β [17] . To test this possibility, we performed a CoIP pull-down experiment and using a RBFOX3-specific antibody observed that RBFOX3 interacts with AP-2β ( Figure 7A-B).…”

Section: Rbfox3 Interacts With Ap-2β To Regulate Htert Expressionmentioning

confidence: 96%

“…The HTERT signaling pathway has been reported as a modulator of cancer cell migration and invasion [16][17][18] . We therefore investigated the role of RBFOX3 on GC cell migration and invasion using wound healing and transwell invasion assays.…”

Section: Rbfox3 Regulates Gc Cell Migration and Invasion In Vitromentioning

confidence: 99%

“…Previous studies have uncovered novel regulators of the HTERT promoter in lung and liver cancer using streptavidin-agarose bead pull down assays [17,20] . To establish whether RBFOX3 interacts with the HTERT promoter in GC as well, we pulled down cytoplasm proteins bound at the HTERT promoter in GC cells using the 5'-biotinylated…”

Section: Rbfox3 Binds To the Htert Promoter In Gc Cellsmentioning

confidence: 99%

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<strong>RBFOX3 Promotes Gastric Cancer Growth and Progression through Activating HTERT Signaling</strong>

Luo¹,

Zhu²,

Luo³

et al. 2020

Preprint

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Tumor invasion, metastasis, and recrudesce remain a considerable challenge in the treatment of gastric cancer (GC). Herein, we first identified that RBFOX3 (RNA binding protein fox-1 homolog 3) was significantly up-regulated in GC tissues and negatively linked to the survival rate of GC patients. RBFOX3 promoted cell division and cell cycle progression in vitro as well as in vivo. Furthermore, RBFOX3 increased cell invasion and migration ability. Interestingly, both the suppression of GC cell multiplication and invasion moderated by the silencing of RBFOX3 was rescued by HTERT up-regulation. Additionally, RBFOX3 augmented the resistance of GC cells to 5-fluorouracil (5-Fu) by repressing RBFOX3. Mechanistically, exogenous up-regulation of RBFOX3 triggered promoter activity and HTERT expression thereby enhancing the division and development of GC cells. Importantly, our findings revealed that RBFOX3 interacted with AP-2β to modulate the HTERT expression as demonstrated by co-immunoprecipitation analysis. In conclusion, our study indicates that high expression of RBFOX3 promotes GC progression and development but predicts worse prognosis by stimulating HTERT signaling. Moreover, the results suggest that the RBFOX3/AP-2β/HTERT pathway is a novel target for the development of therapeutic agents for the prevention and treatment of GC reappearance and metastasis.

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A positive feedback loop between Wnt/β‐catenin signaling and hTERT regulates the cancer stem cell‐like traits in radioresistant nasopharyngeal carcinoma cells

Chen

et al. 2020

J of Cellular Biochemistry

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Radioresistance may be induced by cancer stem cells (CSCs), while the biological traits of CSCs need to be retained by telomerase. The telomerase activity mainly depends on the transcriptional regulation of human telomerase reverse transcriptase (hTERT). Moreover, Wnt/β‐catenin signaling is also considered essential for maintaining the CSC phenotypes. In the previous study, we discovered that the radioresistant nasopharyngeal carcinoma cells CNE‐2R displayed CSC‐like traits, as well as high expression of hTERT and β‐catenin, but whether hTERT and β‐catenin were involved in regulating the CSC‐like traits and radiosensitivity of CNE‐2R cells remained unclear. In this study, our results suggested that hTERT could positively regulate the expression of CSC‐related proteins, as well as the cytoplasm‐ and nucleus‐β‐catenin, but it could not markedly regulate the expression of total β‐catenin in CNE‐2R cells. Meanwhile, Wnt/β‐catenin signaling had a positive regulatory effect on the expression of hTERT and CSC‐related proteins. Moreover, there was a β‐catenin/hTERT protein complex in CNE‐2R cells, indicating that β‐catenin could directly interact with hTERT protein. Our results also revealed that silencing hTERT or suppressing Wnt/β‐catenin signaling could attenuate telomerase activity and radioresistance of CNE‐2R cells; while suppressing Wnt/β‐catenin signaling, the telomerase activity and radioresistance could be reversed through overexpressing hTERT. Taken together, we have outlined a positive feedback loop between Wnt/β‐catenin signaling and hTERT in CNE‐2R cells, which can regulate the telomerase activity and CSC‐like traits, thus regulating the radiosensitivity. Therefore, blocking Wnt/β‐catenin signaling transduction and interfering with hTERT expression may be a promising approach for targeting radioresistant nasopharyngeal carcinoma cells with CSC‐like traits.

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RBFOX3 Promotes Tumor Growth and Progression via hTERT Signaling and Predicts a Poor Prognosis in Hepatocellular Carcinoma

Cited by 32 publications

References 51 publications

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

<strong>RBFOX3 Promotes Gastric Cancer Growth and Progression through Activating HTERT Signaling</strong>

A positive feedback loop between Wnt/β‐catenin signaling and hTERT regulates the cancer stem cell‐like traits in radioresistant nasopharyngeal carcinoma cells

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