Putative Tumor-Suppressive Function of Krüppel-Like Factor 4 in Primary Lung Carcinoma

Hu, Wenxian; Hofstetter, Wayne L.; Li, Hong; Zhou, Yunyun; He, Yong; Pataer, Abujiang; Wang, Li; Xie, Keping; Swisher, Stephen G.; Fang, Bingliang

doi:10.1158/1078-0432.ccr-09-0310

Cited by 112 publications

(108 citation statements)

References 38 publications

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“…These reports suggest that the localization of KLF4 may differ between organs or according to the role of KLF4; however, it is notable that the decrease in KLF4 was associated with the progression of the cancer. With regard to the presence of KLF4 in tumor cells, various studies have revealed decreased KLF4 expression in patients with nasopharyngeal (22), colorectal (24), renal (25), lung (26), cervical (27) and breast cancer (28) who had poor prognosis. Based on these results, KLF4 was suggested to function as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

Prognostic significance of KLF4 expression in gastric cancer

et al. 2016

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“…17,18 In vitro studies indicated that KLF4 inhibits the growth of many cancer cell lines, including lung cancer cells. 19 However, the function and regulation of KLF4 in vivo in the lung and lung cancer are still not known.…”

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confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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“…As a regulatory factor for cell proliferation, KLF4 both induces and inhibits tumor formation. KLF4 is expressed at a low level in many types of human malignant tumors accompanied by hypermethylation and loss of heterozygosity (14,15) and has inhibitory effects on gastric (16), colorectal (17), bladder (18) and lung (19) cancer. However, it is highly expressed in ductal carcinoma in situ and in oral squamous cell carcinoma compared with those in normal tissues (20,21).…”

Section: Discussionmentioning

confidence: 99%

Expression of Krüppel-like factor 4 in breast cancer tissues and its effects on the proliferation of breast cancer MDA-MB-231 cells

Song

Xing

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to detect the expression of Krüppel-like factor 4 (KLF4) in breast cancer tissues and to evaluate the effect on the proliferation of breast cancer MDA-MB-231 cells. The expression of KLF4 protein in 239 breast cancer tissues and 40 paracancerous tissues were detected by an immunohistochemical assay, and its correlation with clinical pathological parameters was analyzed. A eukaryotic expression vector, pcDNA3.1-KLF4, was constructed by transient transfection of breast cancer MDA-MB-231 cells with liposomes (experimental group). The untransfected cells and those transfected with empty plasmid pcDNA3.1 were used as the blank and negative control groups, respectively. The expression of the KLF4 gene and protein in the three groups were detected by reverse transcription polymerase chain reaction and western blotting, respectively. Furthermore, the cell proliferative capacity was detected by an MTT assay. The positive expression rate of KLF4 protein in breast cancer tissues (39.0%, 93/239) was significantly lower than that of paracancerous tissues (77.5%, 31/40) (P<0.05). In addition, KLF4 protein expression in breast cancer tissues was correlated with pathological type, histological grade and lymphatic metastasis (P<0.05). KLF4 mRNA and protein were both expressed by the experimental group, but not by the two control groups. Meanwhile, the proliferative capacity of the experimental group was also significantly decreased. A significant decrease in the positive expression rate of KLF4 protein in breast cancer tissues was correlated with several clinical pathological parameters. In addition, transfection of the KLF4 gene inhibited the proliferation of breast cancer cells, suggesting that this gene is important in the onset and progression of this type of cancer.

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Putative Tumor-Suppressive Function of Krüppel-Like Factor 4 in Primary Lung Carcinoma

Cited by 112 publications

References 38 publications

Prognostic significance of KLF4 expression in gastric cancer

Prognostic significance of KLF4 expression in gastric cancer

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Expression of Krüppel-like factor 4 in breast cancer tissues and its effects on the proliferation of breast cancer MDA-MB-231 cells

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