Krüppel-Like Factor 4 Acts as an Oncogene in Colon Cancer Stem Cell-Enriched Spheroid Cells

Leng, Zhengwei; Tao, Kaixiong; Xia, Qinghua; Tan, Jing-He; Yue, Zhongyi; Chen, Jinhuang; Xi, Hailin; Li, Jie; Zheng, Hao

doi:10.1371/journal.pone.0056082

Cited by 111 publications

(134 citation statements)

References 62 publications

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“…Based on these results, KLF4 was suggested to function as a tumor suppressor. Accordingly, the overexpression of KLF4 was demonstrated to inhibit cell growth, migration, invasion and metastasis in liver, lung and colorectal cancer (29)(30)(31), and induce tumor cell apoptosis in esophageal cancer (32) and bladder cancer (33). These functional investigations also suggested that the loss of KLF4 expression may be involved in the initiation and formation of precancerous lesions in various cancer types.…”

Section: Discussionmentioning

confidence: 90%

Prognostic significance of KLF4 expression in gastric cancer

et al. 2016

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Abstract.To understand the roles of pluripotent stem cell-inducing genes in gastric cancer, the expression of Krüppel-like factor 4 (KLF4), Nanog, octamer-binding transcription factor 4 (Oct4), avian myelocytomatosis viral oncogene homolog (c-Myc) and sex-determining region Y-box 2 (SOX2) was examined using the newly developed gastric carcinoma tissue microarray. The associations between the immunohistochemical expression levels of the pluripotency-inducing factors and the clinicopathological data of 108 patients with gastric cancer were analyzed. No associations were identified between the expression levels of the five pluripotency-inducing factors and the tumor-node-metastasis (TNM) classification or clinicopathological characteristics of the patients. In addition, multivariate analysis revealed no association of Nanog, Oct4, SOX2 or c-Myc with the prognosis of the gastric cancer patients; however, low expression of KLF4 was determined to be an independent negative prognostic factor (P=0.0331), particularly in patients who underwent R0 resection (TNM stages 2 and 3; P=0.0048). In summary, low KLF4 expression was found to be negatively associated with overall survival, and may therefore be a useful prognostic marker in gastric cancer patients. IntroductionGastric cancer is a malignant tumor with a poor prognosis, and the various treatments available at present, including surgery, chemotherapy and radiotherapy, remain unsatisfactory (1). Development of gastric cancer is associated with a number of molecular abnormalities, the majority of which affect the downstream signal transduction pathways involved in cell growth and differentiation (2,3). Investigation into such molecules is expected to provide useful prognostic biomarkers of gastric cancer that will aid in determining the treatment plan for individual patients. For example, methylation of the XIAP-associated factor 1 promoter (4), and expression of 14-3-3σ (5) and miR-200c (6) have been reported to be important for the prediction of poor prognosis in gastric cancer patients; however, further investigation is required.Induced pluripotent stem (iPS) cells are cells that have acquired pluripotency following the introduction of various factors; octamer-binding transcription factor (Oct)3/4 and sex-determining region Y-box 2 (SOX2) plus Krüppel-like factor 4 (KLF4) and avian myelocytomatosis viral oncogene homolog (c-Myc), or Nanog and LIN28 have been shown to induce pluripotency in various murine and human cells (e.g., fibroblasts) (7,8). These pluripotency-inducing factors have been detected in embryonic stem cells, as well as in normal cells and cancer cells, including gastric cancer (9). Although these factors are necessary in order for stem cells to acquire pluripotency, it has been suggested that they may have oncogenic potential in normal cells (10).Expression of SOX2 has been reported to be important for tumorigenicity and chemoresistance (11). However, the inhibition of gastric cancer cell growth and the induction of apoptosis by SOX2 has also been rep...

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Section: Discussionmentioning

confidence: 90%

Prognostic significance of KLF4 expression in gastric cancer

et al. 2016

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“…Each of these factors has been linked to tumor aggressiveness and poor prognosis (Ben-Porath et al 2008;Kim et al 2013;Kareta et al 2015). MYC is one of the most thoroughly studied oncogenes (Cole 1986), and KLF4 has also been classified as an oncogene (Leng et al 2013). Recently, SOX2 was shown to maintain self-renewal and survival of CSCs in multiple tumor types, including squamous cell carcinoma (Boumahdi et al 2014).…”

Section: Cell Fate Determinants As Regulators Of Micsmentioning

confidence: 99%

Distinctive properties of metastasis-initiating cells

2016

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Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies.

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“…Recently, Leng et al reported that Klf4 was over expressed in spheroid-cultured, cancer stem cell-like DLD-1 cells, possibly assigning Klf4 a tumor growth promoting role [43]. Possible effects on cancer stem cells were not investigated in our study, although we have previously shown that GLV-1h68 replicates preferentially in human breast cancer stem-like cells [44].…”

Section: Discussionmentioning

confidence: 65%

Vaccinia Virus-Mediated Expression of Transcription Factor Klf4 Enhances Oncolytic Virotherapy of Colorectal Cancer

Aladar¹

2014

JHVRV

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Colorectal cancer (CRC) detected at an early stage has a good prognosis, however, recurrence of the disease is prevalent and late stage CRC (stage IIIC and IV) has observed 5-year survival rates of 28% and 6%, respectively. Oncolytic virotherapy has been explored as a potential treatment modality in cancer therapy for its safety and tumor specificity. We recently reported that oncolytic vaccinia virus GLV-1h68 efficiently infected, replicated in, and lysed different colorectal cancer cell lines derived from patients at different stages of the disease in culture and mouse xenograft models. However, the cytotoxicity of GLV-1h68 was cell linedependent and, in particular, xenograft tumors of the colorectal cancer cell line HT-29 did not respond favorably to oncolytic treatment with GLV-1h68. Here we report on the generation of recombinant vaccinia viruses expressing the colorectal tumor suppressor Klf4. We show that a single injection of vaccinia virus expressing Klf4 led to significant tumor growth inhibition of HT-29 human colon cancer xenografts in comparison to treatment with GLV-1h68. Furthermore, virus-mediated expression of a membrane-permeable Klf4-TAT fusion protein, further improved the anti-tumoral effects. This is the first report demonstrating that arming oncolytic viruses with the colorectal tumor suppressor Klf4 led to improved therapy in a human colon cancer xenograft model.

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Krüppel-Like Factor 4 Acts as an Oncogene in Colon Cancer Stem Cell-Enriched Spheroid Cells

Cited by 111 publications

References 62 publications

Prognostic significance of KLF4 expression in gastric cancer

Prognostic significance of KLF4 expression in gastric cancer

Distinctive properties of metastasis-initiating cells

Vaccinia Virus-Mediated Expression of Transcription Factor Klf4 Enhances Oncolytic Virotherapy of Colorectal Cancer

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