KLF4 is a Novel Candidate Tumor Suppressor Gene in Pancreatic Ductal Carcinoma

Abstract

Ductal pancreatic carcinoma (DPC) is a deadly disease with an incidence of 9 cases in 100,000 people per year and a mortality rate close to 100%. Allelic losses in the long arm of chromosome 9 are commonly encountered in many human malignancies but no data are yet available about DPC. We screened 40 lasermicrodissected DPC samples and 6 pre-invasive lesions for 9 microsatellite mapping markers of region 9q21.3 through 9q34.2. A small overlapping region of deletion, spanning 8 million base pairs, was identified between D9S127 and D9S105. Two genes, RSG3 and KLF4, mapped to 9q31.1 through 9q32, were further investigated. A highly significant association was found between KLF4 gene expression levels and genomic status. Similarly, absence of immunohistochemical expression of KLF4 protein was found in 86.8% cases of DPC (33/ 38). Overexpression of KLF4 in a human pancreatic carcinoma cell line induced a significant decrease in the proliferation associated with up-regulation of p21 and the down-regulation of cyclin D1. In conclusion, we identified a novel oncosuppressor region located at the 9q 31.1-3 locus that is lost in DPC at high frequency. Loss of KLF4 expression is closely related to the genomic loss, and its restoration inhibits cancer cell proliferation, suggesting a key suppressor role in pancreatic tumorigenesis. Pancreatic cancer is the fifth leading cause of cancerrelated death in both men and women in the Western world, being responsible for 5% of all cancer-related deaths.1 The lack of reliable early diagnostic methods and effective therapeutic regimens makes the mortality rates in persons with pancreatic carcinoma virtually the same as the incidence rates. A radical surgical approach is possible in only 10% of cases, and adjuvant therapies are virtually ineffective.2 A better understanding of the molecular mechanisms leading to pancreatic tumorigenesis may provide new markers for early diagnosis and potential targets for therapeutic intervention.Ductal pancreatic carcinoma (DPC) is by far the most common pancreatic tumor type, accounting for about 90% of all pancreatic malignancies. At present, a molecular model of DPC development has been proposed; it involves key genes, such K-ras, HER2neu, p16, p53, and DPC4 (smad4). Activating mutations in the K-ras oncogene and the overexpression of Her-2/neu gene are considered "early" genetic events because they occur in pre-invasive lesions (pancreatic intra-epithelial neoplasias, or PanINs) 3,4 and are followed by homozygous deletions in the p16 tumor suppressor gene locus. 5,6 Later in the tumor's progression, inactivations of p53 and DPC4 tumor suppressor genes are thought to be key events that lead to fully transformed phenotypes (carcinoma in situ, or PanIN-3). 7-11Wide genomic instability characterizes DPC, as has been documented by the large collection of cytogenetic abnormalities reported in the literature. [12][13][14][15][16][17] Among these, 9p (p16 locus), 17p (p53 locus), and 18q (DPC4 locus) have been reported to have been deleted in more than 60%...

Krüppel-like factors in mammalian stem cells and development

“…Mechanistically, KLFs have a direct impact on almost every aspect of cancer biology: regulation of the cell cycle, apoptosis, Wnt/β-catenin signaling, RAS signaling, NOTCH signaling, oncogenic transformation, tumor metastasis, and microenvironment (Tetreault et al, 2013). For instance, KLF4, a key regulator of normal cell proliferation, inhibits tumor growth in various cancers such as pancreatic, colorectal, neuroblastoma and lung cancers by inducing the expression of CDK inhibitors and inhibiting cyclin D1 and FOXM1 expression (Kong et al, 2013;Shum et al, 2013;Wei et al, 2008;Zammarchi et al, 2011). Conversely, KLF5 promotes tumor cell growth by upregulating CCNA2, CDT1 and E2F3, all of which are key cell cycle genes Takagi et al, 2012).…”

Degrons in cancer

“…KLF4 plays both tumor suppressor and tumor-promoting roles in cancer as a result of its wide range of targets and its function in several key pathways important for maintaining control over cell proliferative potential. Tumor suppressor functions of KLF4 relate to its ability to induce expression of genes encoding the CDK inhibitors p21 WAF1 and p27 KIP1 and to reduce expression of the genes encoding cyclin D1, cyclin B, and FOXM1 (310)(311)(312), negatively regulating proliferation in gastric cancer, bladder cancer, lymphoma, and lung carcinomas, among others (313)(314)(315)(316). Tumor-promoting activity arises from the ability of KLF4 to repress the expression of the gene encoding p53 (317) and, consequently, reduce expression of p53 target genes encoding proapoptotic proteins, such as BAX (318).…”

Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis

“…Negative regulation of KLF4 by Notch signalling has been observed in intestinal epithelium or colorectal cancer cells 37,38 and these results are in favour of the tumour suppressor role of KLF4 in colorectal cancer cells 39 . In contrast to the tumour suppressor role of KLF4 in colorectal cancer cells/intestinal epithelium and pancreatic cancer [37][38][39][40][41] , other groups have demonstrated the oncogenic role of KLF4 in breast cancer and HNC [42][43][44] . These findings are consistent with our discovery that KLF4 plays an oncogenic role, especially in HNSCC 44 .…”