Transforming Growth Factor-β-Induced RBFOX3 Inhibition Promotes Epithelial-Mesenchymal Transition of Lung Cancer Cells

Kim, Yong-Eun; Kim, Jong Ok; Park, Ki-Sun; Won, Minho; Kim, Kyoon Eon; Kim, Kee K.

doi:10.14348/molcells.2016.0150

Cited by 19 publications

(18 citation statements)

References 26 publications

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“…The TGF-beta signaling pathway is a classical tumorigenesis-related pathway; it exerts dual and opposing roles in oncogenesis, inhibiting cell proliferation in early tumors and inducing tumor progression and metastasis in advanced cancer (Seoane and Gomis, 2017;Batlle and Massague, 2019). Previous studies have shown that RBPs can interact with the TGF-beta signaling pathway to regulate lung carcinogenesis (Kim et al, 2016;Bai et al, 2019). These results suggest that RBPs can affect the growth of tumor cells by regulating multiple biological processes, such as the TGF-beta signaling pathway, RNA metabolism, and RNA processing.…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

Xue

Gao

et al. 2020

Front. Genet.

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Lung cancer is the leading cause of cancer-related deaths worldwide. Dysregulation of RNA binding proteins (RBPs) has been found in a variety of cancers and is related to oncogenesis and progression. However, the functions of RBPs in lung squamous cell carcinoma (LUSC) remain unclear. In this study, we obtained gene expression data and corresponding clinical information for LUSC from The Cancer Genome Atlas (TCGA) database, identified aberrantly expressed RBPs between tumors and normal tissue, and conducted a series of bioinformatics analyses to explore the expression and prognostic value of these RBPs. A total of 300 aberrantly expressed RBPs were obtained, comprising 59 downregulated and 241 upregulated RBPs. Functional enrichment analysis indicated that the differentially expressed RBPs were mainly associated with mRNA metabolic processes, RNA processing, RNA modification, regulation of translation, the TGF-beta signaling pathway, and the Toll-like receptor signaling pathway. Nine RBP genes (A1CF, EIF2B5, LSM1, LSM7, MBNL2, RSRC1, TRMU, TTF2, and ZCCHC5) were identified as prognosis-associated hub genes by univariate, least absolute shrinkage and selection operator (LASSO), Kaplan-Meier survival, and multivariate Cox regression analyses, and were used to construct the prognostic model. Further analysis demonstrated that high risk scores for patients were significantly related to poor overall survival according to the model. The area under the time-dependent receiver operator characteristic curve of the prognostic model was 0.712 at 3 years and 0.696 at 5 years. We also developed a nomogram based on nine RBP genes, with internal validation in the TCGA cohort, which showed a favorable predictive efficacy for prognosis in LUSC. Our results provide novel insights into the pathogenesis of LUSC. The nine-RBP gene signature showed predictive value for LUSC prognosis, with potential applications in clinical decision-making and individualized treatment.

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Section: Discussionmentioning

confidence: 99%

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

Xue

Gao

et al. 2020

Front. Genet.

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“…Although previous studies reported RBFOX3 was exclusively expressed in post-mitotic neurons of the central nervous system, recent studies indicated that RBFOX3 is also expressed in some non-neuronal tissues [30, 31]. Another study showed that RBFOX3 expression was inhibited during TGF-β-induced epithelial-mesenchymal transition (EMT) in lung cancer [32]. Nevertheless, the cellular function of RBFOX3 in tumorigenesis remains unclear.…”

Section: Discussionmentioning

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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“…34,35 It was previously shown, that certain cytokines such as IL-6, IL-8 or TGFb initiate and/or sustain the mesenchymal cancer cell state. [36][37][38] We used TGFb to induce EMT in A549 cells, which express low levels of endogenous BOK. When exogenous BOK expression was induced in those cells, TGFbinduced phenotypic change was prevented ( Fig.…”

Section: Molecular Cancer Biologymentioning

confidence: 99%

BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

Moravcikova

Kr̆epela

Donnenberg

et al. 2017

Intl Journal of Cancer

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Since the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (P<0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (P=0.004, n=35) and three (P=0.031, n=39) as well as in tumors with metastases to hilar (pN1) (P=0.047, n=31) and mediastinal/subcarinal lymph nodes (pN2) (P=0.021, n=18) as opposed to grade one tumors (P=0.688, n=7) and tumors without lymph node metastases (P=0.112, n=51). Importantly, in lymph node positive patients, BOK expression greater than the median value was associated with longer survival (P=0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients.

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Transforming Growth Factor-β-Induced RBFOX3 Inhibition Promotes Epithelial-Mesenchymal Transition of Lung Cancer Cells

Cited by 19 publications

References 26 publications

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

Integrated Analysis of the Functions and Prognostic Values of RNA Binding Proteins in Lung Squamous Cell Carcinoma

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

BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

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