The transcription factor Krüppel-like factor 5 promotes cell growth and metastasis via activating PI3K/AKT/Snail signaling in hepatocellular carcinoma

An, Tingting; Dong, Tianxiu; Zhou, Haoxin; Chen, Yaodong; Zhang, Jiuwei; Li, Zizhuo; Yang, Xiuhua

doi:10.1016/j.bbrc.2018.11.084

Cited by 21 publications

(28 citation statements)

References 34 publications

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“…KLF5 regulates numerous key cellular processes, including proliferation, angiogenesis, pluripotency, inflammation, and migration . In cancer, KLF5 is typically pro‐proliferative by regulating cell cycle progression . Recently, studies have demonstrated that knockdown of KLF5 suppresses hypoxia‐induced cisplatin resistance in NSCLC cells .…”

Section: Introductionsupporting

confidence: 91%

“…demonstrated that IGF‐1 decreases radiation‐induced phosphorylation of Chk1 at S345 or S296 via the PI3K/AKT pathway . Notably, various studies have confirmed that KLF5 plays critical roles in the PI3K/Akt/mTOR pathway . Moreover, phosphorylation of Chk2 at T68 in response to DNA damage occurs in ATM‐deficient cells, suggesting that kinases other than ATM may be involved .…”

Section: Discussionmentioning

confidence: 99%

“…27 Notably, various studies have confirmed that KLF5 plays critical roles in the PI3K/Akt/mTOR pathway. 11,13 Moreover, phosphorylation of Chk2 at T68 in response to DNA damage occurs in ATM-deficient cells, suggesting that kinases other than ATM may be involved. 28 Thus, this study provides proof for further investigation of the role of KLF5 in regulating the phosphorylation of Chk1 and Chk2.…”

Section: Discussionmentioning

confidence: 99%

“…10 In cancer, KLF5 is typically pro-proliferative by regulating cell cycle progression. 11,12 Recently, studies have demonstrated that knockdown of KLF5 suppresses hypoxia-induced cisplatin resistance in NSCLC cells. 13 In the intestine, KLF5 may affect DNA damage repair pathways.…”

Section: Introductionmentioning

confidence: 99%

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Knockdown of KLF5 promotes cisplatin‐induced cell apoptosis via regulating DNA damage checkpoint proteins in non‐small cell lung cancer

et al. 2019

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Background Previous research has revealed that Krüppel‐like factor 5 ( KLF5 ) may affect DNA damage repair pathways; however, the associated molecular mechanisms are unclear. Methods The expression of KLF5 was studied by immunohistochemical staining in paired tumour and normal tissues from 90 patients with ESCC. We studied the effects of KLF5 knockdown on cell proliferation and apoptosis with or without cisplatin treatment in A549 and H1299 cell lines. Moreover, we examined the effect of KLF5 on the DNA damage response. Results KLF5 was significantly overexpressed in non‐small cell lung cancer (NSCLC) tissues, and high KLF5 expression predicted poor prognosis for NSCLC patients. The inhibition of KLF5 markedly augmented cisplatin‐induced cell apoptosis. In addition, we observed that KLF5 knockdown could decrease DNA repair potential by inhibiting H2AX S139 phosphorylation in response to cisplatin. Moreover, silencing of KLF5 in NSCLC cell lines inhibited the phosphorylation of checkpoint kinases Chk1 S345 and Chk2 T68. KLF5 knockdown permits cells with broken or damaged DNA strands to enter mitosis by inhibiting the activation of H2AX, Chk1 and Chk2, resulting in mitotic catastrophe. Conclusion KLF5 plays a significant role in the DNA damage response by regulating DNA damage checkpoint proteins. Inhibition of KLF5 may be a potential therapeutic target for NSCLC patients with cisplatin resistance.

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Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Knockdown of KLF5 promotes cisplatin‐induced cell apoptosis via regulating DNA damage checkpoint proteins in non‐small cell lung cancer

et al. 2019

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“…As shown in the present study, colon cancer cells with high KLF5 expression might exhibit CSC‐like properties, at least in part, by modulating c‐Myc expression. Additionally, previous studies indicated that KLF5 is involved in EMT 35,36 . Therefore, cells with high KLF5 expression might acquire more aggressive metastatic properties during the course of cancer progression than other cells.…”

Section: Discussionmentioning

confidence: 96%

High expression of Krüppel‐like factor 5 is associated with poor prognosis in patients with colorectal cancer

et al. 2020

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Krüppel‐like factor 5 (KLF5) plays an oncogenic role and has diverse functions in cancer cells. However, correlation between KLF5 and clinical outcome has not been determined in patients with colorectal cancer and colorectal liver metastasis. Herein, we analyzed 65 patients with colorectal cancer who developed colorectal liver metastasis. Clinical effects were assessed through immunohistochemical analysis of primary colorectal cancer lesions and metastatic liver lesions. High expression of KLF5 in these tissues correlated with the presence of vascular invasion, elevated serum carbohydrate antigen 19‐9 levels, large diameters of metastatic liver tumors, and poor prognosis following surgery. Multivariate analyses revealed that high expression of KLF5 was an independent prognostic factor. Increased expression of KLF5 in both colorectal cancer primaries and colorectal liver metastasis was significantly associated with shorter overall survival time and time to surgical failure. Krüppel‐like factor 5 expression positively correlated with Ki‐67 and c‐Myc expression in colorectal cancer tissues. In vitro experiments with colon cancer cell lines showed that siRNA knockdown of KLF5 inhibited cell proliferation. Western blot analyses revealed that knockdown of KLF5 expression reduced cyclin D1 and c‐Myc expression. It also impaired the stem cell‐like properties of cancer cells in tumorsphere formation assays. Furthermore, anoikis assay indicated that KLF5 contributed to anoikis resistance. High KLF5 expression is associated with poor prognosis in patients with colorectal cancer and liver metastasis by promoting cell proliferation and cancer stem cell‐like properties.

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Direct Conversion of Human Endothelial Cells Into Liver Cancer‐Forming Cells Using Nonintegrative Episomal Vectors

et al. 2022

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Liver cancer is an aggressive cancer associated with a poor prognosis. Development of therapeutic strategies for liver cancer requires fundamental research using suitable experimental models. Recent progress in direct reprogramming technology has enabled the generation of many types of cells that are difficult to obtain and provide a cellular resource in experimental models of human diseases. In this study, we aimed to establish a simple one‐step method for inducing cells that can form malignant human liver tumors directly from healthy endothelial cells using nonintegrating episomal vectors. To screen for factors capable of inducing liver cancer‐forming cells (LCCs), we selected nine genes and one short hairpin RNA that suppresses tumor protein p53 (TP53) expression and introduced them into human umbilical vein endothelial cells (HUVECs), using episomal vectors. To identify the essential factors, we examined the effect of changing the amounts and withdrawing individual factors. We then analyzed the proliferation, gene and protein expression, morphologic and chromosomal abnormality, transcriptome, and tumor formation ability of the induced cells. We found that a set of six factors, forkhead box A3 (FOXA3), hepatocyte nuclear factor homeobox 1A (HNF1A), HNF1B, lin‐28 homolog B (LIN28B), MYCL proto‐oncogene, bHLH transcription factor (L‐MYC), and Kruppel‐like factor 5 (KLF5), induced direct conversion of HUVECs into LCCs. The gene expression profile of these induced LCCs (iLCCs) was similar to that of human liver cancer cells, and these cells effectively formed tumors that resembled human combined hepatocellular–cholangiocarcinoma following transplantation into immunodeficient mice. Conclusion: We succeeded in the direct induction of iLCCs from HUVECs by using nonintegrating episomal vectors. iLCCs generated from patients with cancer and healthy volunteers will be useful for further advancements in cancer research and for developing methods for the diagnosis, treatment, and prognosis of liver cancer.

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The transcription factor Krüppel-like factor 5 promotes cell growth and metastasis via activating PI3K/AKT/Snail signaling in hepatocellular carcinoma

Cited by 21 publications

References 34 publications

Knockdown of KLF5 promotes cisplatin‐induced cell apoptosis via regulating DNA damage checkpoint proteins in non‐small cell lung cancer

Knockdown of KLF5 promotes cisplatin‐induced cell apoptosis via regulating DNA damage checkpoint proteins in non‐small cell lung cancer

High expression of Krüppel‐like factor 5 is associated with poor prognosis in patients with colorectal cancer

Direct Conversion of Human Endothelial Cells Into Liver Cancer‐Forming Cells Using Nonintegrative Episomal Vectors

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