KLF4 deletion alters gastric cell lineage and induces MUC2 expression

Yu, Ting; Chen, X; Lin, Tian; Liu, J; Li, M; Zhang, W; Xu, Xiao‐Quan; Zhao, Weiqi; Liu, M; Napier, Dana; Wang, C; Evers, B. Mark; Liu, C

doi:10.1038/cddis.2016.158

Cited by 34 publications

(28 citation statements)

References 23 publications

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“…Numerous studies have shed light on tumor-targeting therapies using miRNAs as a novel diagnostic and therapeutic tools (7,8,12,25,28). In the present study, the downregulation of Klf4 and miR-31 was consistently observed in HCC tissues and they may thus serve as potential diagnostic markers and therapeutic targets for HCC.…”

Section: Discussionmentioning

confidence: 99%

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

Tian

Yao

Liu

et al. 2016

International Journal of Molecular Medicine

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MicroRNAs (miRNAs or miRs) are short, endogenous non-coding RNA molecules, demonstrating abnormal expression in cancer initiation and progression. In this study, we profiled 18 differentially regulated miRNAs, including miRNA-31, using miRNA array. Kruppel (or Krüppel)-like factor 4 (Klf4) is a transcription factor and putative tumor suppressor. Both were found to be significantly downregulated in liver cancer tissues and cells. However, little is known about the correlation between Klf4 and miRNA-31 in hepatocellular carcinoma (HCC). The mRNA expression of Klf4 was decreased and inversely associated with the clinical stage, T classification and hepatitis B in patients with HCC, while the expression of miR-31 was lower (r=0.326, P=0.018). Using cell counting kit 8 (CCK8) and Transwell migration assays, we found that Klf4 and miR-31 inhibited the proliferation and metastasis of liver cancer cells. Moreover, we demonstrated that Klf4 directly binds to the promoter of miR-31 and activates its transcription. In vitro experiments confirmed that Klf4 regulated miR-31 and thereby inhibited HCC cell growth and metastasis. Taken together, our findings indicate that Klf4 directly regulates miR-31 in HCC. Thus, miR-31 may serve as a potential diagnostic marker and therapeutic target in HCC.

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Section: Discussionmentioning

confidence: 99%

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

Tian

Yao

Liu

et al. 2016

International Journal of Molecular Medicine

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“…A functional experimental study showed that KLF4 overexpression significantly promoted apoptosis and inhibited cell cycle progression in vitro, and reduced the tumorigenicity of GC in vivo . Besides, KLF4 inhibits cell proliferation, promotes cell differentiation and is closely related to tumor development . Targeting KLF4 in advanced solid tumors has been approved for clinical trials .…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Besides, KLF4 inhibits cell proliferation, promotes cell differentiation and is closely related to tumor development. 21,22 Targeting KLF4 in advanced solid tumors has been approved for clinical trials. 7 In this study, we show that KLF4 expression is lower in both GC patient' samples and cell lines compare to controls.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to a large number of studies, we found that KLF4 is related to the regulation of cell differentiation and proliferation. [21][22][23][24][25] Therefore, the GC cells AGS and the normal gastric epithelial cells GES-1 were transiently transfected with the empty vector plasmid αSR and the plasmid with H pylori CagA-wt (3.0 µg), respectively, and then the cell proliferation and migration were detected. The MTT assay found that when CagA-wt was overexpressed, the proliferation abilities of GES-1 and AGS cells were significantly enhanced ( Figure 3A,B).…”

Section: And Ags Cells Promoted Behavioral Changementioning

confidence: 99%

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Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1‐mediated DNA methylation mechanism

Zhao

Liu

et al. 2020

Cancer Medicine

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Krüppel‐like factor 4 (KLF4) has a tumor suppressor role in the progression of gastric cancer (GC), and inhibition or loss of KLF4 expression was identified in GC. The aim of this study was to explore the new molecular mechanism of KLF4 inactivation in gastric cancer. Herein, we report that Helicobacter pylori infection or Cag pathogenicity island protein A (CagA) gene transduction resulted in KLF4 expression downregulation and promoted gastric epithelial cell and gastric cancel cell proliferation, migration, and colony formation. Mechanistically, we found that CagA gene transduction led to DNA methylation of the KLF4 promoter, an effect that was relevant to the significant downregulation of TET1 expression. Causally, knockdown of TET1 expression decreased KLF4 expression, whereas overexpression of TET1 had the opposite effect. Clinically, we found that KLF4 expression and the 5‐hmC levels were lower in GC cells with H pylori infection than in GC cells without H pylori infection. Thus, our study not only sheds new light on how H pylori infection promotes the progression of GC but also elucidates a novel mechanism of KLF4 inactivation in GC pathogenesis. During pathogenesis, an alteration in the H pylori/CagA‐TET1‐KLF4 signaling pathway plays a critical role, suggesting that this pathway may be a prospective target for gastric carcinoma intervention and therapy.

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“…Thus, understanding of the mechanism by which chemotherapy resistance occurs contributes to the development of novel therapeutic strategies for overcoming advanced PDAC. KLF4 has been identified as a tumor suppressor in diverse types of cancer (13)(14)(15), including PDAC (5). In the pancreas, KLF4 is predominantly expressed in PDAC and regulates the expression of cytokeratin-19, a specific marker for PDAC (16).…”

Section: Discussionmentioning

confidence: 99%

Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma

Wang

Chen

Lin

et al. 2017

International Journal of Oncology

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with broad resistance to chemotherapeutic drugs. Krüppel-like factor 4 (KLF4) is a candidate tumor suppressor in PDAC. However, the precise role of KLF4 in gemcitabine resistance of PDAC remains largely unclear. In this study, we demonstrated that gemcitabine inhibited KLF4 expression. Moreover, gemcitabine also reduced the levels of miR‑200b and miR‑183, but promoted ZEB1 expression in PDAC cells. KLF4 knockdown blocked the expression of miR‑200b and miR‑183, and inversely, KLF4 overexpression promoted the expression of miR‑200b and miR‑183, suggesting that KLF4 positively regulated the expression of miR‑200b and miR‑183. Moreover, KLF4 knockdown enhanced ZEB1 expression and gemcitabine resistance while KLF4 overexpression induced the opposite effect. ChIP assays verified that KLF4 positively regulated the expression of miR‑200b and miR‑183 by directly binding to their promoters. Then, miR‑200b and miR‑183 directly inhibited ZEB1 expression by targeting its 3'UTR region. ZEB1 knockdown attenuated gemcitabine resistance in PDAC cells. KLF4 overexpression promoted gemcitabine sensitivity of PDAC in vivo by negatively regulating ZEB1 expression. Our results revealed that novel crosstalk between KLF4 and ZEB1 regulated gemcitabine resistance in PDAC.

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KLF4 deletion alters gastric cell lineage and induces MUC2 expression

Cited by 34 publications

References 23 publications

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

Klf4 inhibits tumor growth and metastasis by targeting microRNA-31 in human hepatocellular carcinoma

Helicobacter pylori infection leads to KLF4 inactivation in gastric cancer through a TET1‐mediated DNA methylation mechanism

Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma

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