TFF1 activates p53 through down-regulation of miR-504 in gastric cancer

Soutto, Mohammed; Chen, Zheng; Saleh, Mohamed A.; Katsha, Ahmed; Zhu, Shoumin; Zaika, Alexander; Belkhiri, Abbes; El–Rifai, Wael

doi:10.18632/oncotarget.2156

Cited by 55 publications

(55 citation statements)

References 48 publications

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“…Recently, TFF1 has been found to be able to activate p53 by downregulating miR-504 [31]. Another study has reported that TFF1 can inhibit cell proliferation by delaying G1/S cell phase transition while paradoxically increasing the expression of cyclin D1 [32].…”

Section: Discussionmentioning

confidence: 99%

Heterodimeric interaction between GKN2 and TFF1 entails synergistic antiproliferative and pro-apoptotic effects on gastric cancer cells

et al. 2017

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Background GKN2 and TFF1 form a heterodimer that is only generated in the mucus-secreting cells of the normal stomach. The formation of this heterodimer is frequently disrupted in gastric cancer. However, the precise roles of GKN2 alone and in the heterodimer with TFF1 as well as the contributions of GKN2 and the heterodimer to gastric carcinogenesis are poorly understood. Methods Cell viability, proliferation, and apoptosis were analyzed in AGS, MKN1, MKN28, and MKN45 gastric cancer cells transfected with GKN2 and/or TFF1 using MTT, BrdU incorporation, and apoptosis assays, respectively. In addition, cell viability was examined in HFE-145 non-neoplastic gastric epithelial cells after GKN2 and/or TFF1 silencing. Furthermore, the cell cycle and the expression of cell cycle and apoptosis related proteins were assessed. The interaction between GKN2 and TFF1 was confirmed by co-immunoprecipitation. Immunohisto-chemistry was employed to explore TFF1 expression in 169 gastric cancer tissues. Results Co-transfection with GKN2 and TFF1 significantly inhibited cell viability and proliferation by inducing G1/S cell cycle arrest and suppressing positive cell cycle regulators. Simultaneous knockdown of GKN2 and TFF1 in HFE-145 cells resulted in markedly increased cell viability. Moreover, the interaction of GKN2 and TFF1 promoted cell death by enhancing caspase-3/7 activity and upregulating pro-apoptotic proteins. At the mRNA level, GKN2 and TFF1 were found to be positively correlated in non-tumor and tumor samples. Immunohistochemistry revealed loss of TFF1 expression in 128 (75.73%) of 169 gastric cancers. There was a borderline-significant association between GKN2 and TFF1 protein expression in gastric cancers (P = 0.0598). Conclusion Collectively, our data demonstrated that the interaction between GKN2 and TFF1 can have synergistic antiproliferative and pro-apoptotic effects on gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Heterodimeric interaction between GKN2 and TFF1 entails synergistic antiproliferative and pro-apoptotic effects on gastric cancer cells

et al. 2017

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“…In agreement with a putative oncogenic role, miR-504 is overexpressed in a variety of cancers (4,(37)(38)(39)(40). However, relatively little is known about the mechanisms that control miR-504 expression, beyond its downregulation by the secreted factors CTGF and TFF1 (38,39).…”

Section: Fgf13 Depletion Augments Nucleolar Size and Increases Rrna Andmentioning

confidence: 99%

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

Bublik

Bursać

Sheffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The microRNA miR-504 targets TP53 mRNA encoding the p53 tumor suppressor. miR-504 resides within the fibroblast growth factor 13 (FGF13) gene, which is overexpressed in various cancers. We report that the FGF13 locus, comprising FGF13 and miR-504, is transcriptionally repressed by p53, defining an additional negative feedback loop in the p53 network. Furthermore, we show that FGF13 1A is a nucleolar protein that represses ribosomal RNA transcription and attenuates protein synthesis. Importantly, in cancer cells expressing high levels of FGF13, the depletion of FGF13 elicits increased proteostasis stress, associated with the accumulation of reactive oxygen species and apoptosis. Notably, stepwise neoplastic transformation is accompanied by a gradual increase in FGF13 expression and increased dependence on FGF13 for survival ("nononcogene addiction"). Moreover, FGF13 overexpression enables cells to cope more effectively with the stress elicited by oncogenic Ras protein. We propose that, in cells in which activated oncogenes drive excessive protein synthesis, FGF13 may favor survival by maintaining translation rates at a level compatible with the protein qualitycontrol capacity of the cell. Thus, FGF13 may serve as an enabler, allowing cancer cells to evade proteostasis stress triggered by oncogene activation.proteostasis | p53 | miR-504 | FGF13 | ribosomal biogenesis

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“…4, miRNAs can control cell cycle progression after DNA damage by targeting CHK1 [70][71][72][73][74], p53 [75,76], retinoblastoma 1 serine phosphates from human chromosome 3 (RBSP3) [77], cyclin D [73,78,79], CDC25a [80][81][82], p21, CDK2 [83][84][85], WEE1, PLK1, and so on. One study showed that RBSP3 is a target gene of miR-100.…”

Section: Mirnas Regulate Ddr Effectorsmentioning

confidence: 99%