Krüppel-Like Factor 5 Mediates Cellular Transformation During Oncogenic KRAS-Induced Intestinal Tumorigenesis

Nandan, Mandayam O.; McConnell, Beth B.; Ghaleb, Amr M.; Bialkowska, Agnieszka B.; Sheng, Hongmiao; Shao, Jinyi; Babbin, Brian A.; Robine, Sylvie; Yang, Vincent W.

doi:10.1053/j.gastro.2007.10.023

Cited by 115 publications

(138 citation statements)

References 38 publications

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“…Because recent studies showed a substantial overexpression of KLF5 in KRAS-mutated HCT116 colon cancer cells, we used this particular colon cancer cell line as a positive control (13). Interestingly, our results show that, at a similar cell density, KLF5 is overexpressed in pancreatic cancer cell lines and, furthermore, exceeds the KLF5 expression levels of HCT116 colon cancer cells, suggesting that KRAS may play a pivotal role in mediating KLF5 in pancreatic cancer (Fig.…”

Section: Expression Of Klf5 In Pancreatic Cancermentioning

confidence: 73%

“…The involvement of KRAS/MAPK/Erk signaling in the upregulation of KLF5 has recently been elegantly shown in a model with KRAS-inducible colon cancer cells (13). In that model, specific inhibition of MAPK/Erk using Erk1/2 signaling inhibitors robustly abrogated KRAS-mediated KLF5 induction, whereas other pathways were not involved in this process.…”

Section: Discussionmentioning

confidence: 97%

“…Importantly, the implication of KLF5 in mediating anchorage-independent cancer cell growth has recently been elegantly shown by Nandan and colleagues, a process that was promoted via KRAS activation (13). However, the opposite effect in terms of up-regulating KLF5 by cell density or anchorage-independent growth has not yet been described.…”

Section: Discussionmentioning

confidence: 99%

“…In that particular study, the effect of KLF5 induction was inhibited by blocking MAPK/Erk using UO126 (13). We therefore investigated whether signaling inhibition could alter KLF5 expression, expecting that blocking MAPK/Erk would reduce KLF5.…”

Section: Identification Of Signaling Pathways Involved In Klf5 Regulamentioning

confidence: 99%

“…Because pancreatic cancers frequently harbor activating KRAS mutations (11), which consecutively activate MEK/MAPK/Erk signaling (12), we hypothesized that KLF5 could be up-regulated in this cancer entity. In favor of this hypothesis are results from a recently published study demonstrating that KRAS activation promotes KLF5 up-regulation in human colon cancer (HCT116) cells (13). Moreover, because hypoxia-mediated and cytokine-mediated activation of the oncogenic transcription factor hypoxia-inducible factor-1α (HIF-1α) is frequently encountered in pancreatic tumors, we also hypothesized that the interleukin (IL)-1β system and/or HIF-1α may be involved in the regulation of KLF5 expression (14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Krüppel-like factor 5 (KLF5) is a transcription factor involved in cell transformation, proliferation, and carcinogenesis that can be up-regulated by RAS mutations. However, controversy persists as to whether it functions as a tumor suppressor or as an oncogene. Because KRAS is frequently mutated in pancreatic cancer, we investigated the regulation of KLF5 in this cancer entity. Our results show that KLF5 is overexpressed in pancreatic cancer cells and exceeds KLF5 expression of KRAS-mutated colon cancer cells. Surprisingly, inhibition of B-Raf/C-Raf or MAPK/Erk did not reduce KLF5 levels, suggesting that KLF5 expression is not promoted by KRAS-Raf-MEK-Erk signaling in pancreatic cancer. This finding is in striking contrast to reports on MEK-Erk-mediated KLF5 induction in colon cancer cells. Moreover, KLF5 expression levels neither correlated with the mutational status of KRAS nor with MEK phosphorylation in pancreatic cancer cells. Importantly, KLF5 was significantly up-regulated by interleukin (IL)-1β or hypoxia. The IL-1 β-mediated induction of KLF5 was diminished by blocking the p38 pathway. In addition, blocking IL-1R reduced the constitutive KLF5 expression, suggesting an autocrine activation loop. Moreover, KLF5 coimmunoprecipitated with hypoxia-inducible factor-1α (HIF-1α) and HIF-1α siRNA reduced constitutive KLF5. Similarly, KLF5 siRNA reduced the expression of the HIF-1α target gene GLUT-1. Furthermore, KLF5 expression was significantly elevated by high cell density, by anchorage-independent cell growth, and in tumor spheroids. Down-regulation of KLF5 by RNAi reduced the expression of the target genes, survivin, and platelet-derived growth factor-A. In conclusion, overexpression of KLF5 in human pancreatic cancer cells is not mediated by KRAS/Raf/ MAPK/Erk signaling, but involves the IL-1β/IL-1R system, p38, and the transcription factor

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Section: Expression Of Klf5 In Pancreatic Cancermentioning

confidence: 73%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Signaling Pathways Involved In Klf5 Regulamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Mori

Moser

Lang

et al. 2009

Molecular Cancer Research

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Identifying Diagnostic MicroRNAs and Investigating Their Biological Implications in Rectal Cancer

Kim

Chen

et al. 2021

JAMA Netw Open

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EGFR and Prion protein promote signaling via FOXO3a‐KLF5 resulting in clinical resistance to platinum agents in colorectal cancer

et al. 2019

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Epidermal growth factor receptor ( EGFR ) supports colorectal cancer progression via oncogenic signaling. Anti‐ EGFR therapy is being investigated as a clinical option for colorectal cancer, and an observed interaction between EGFR and Prion protein has been detected in neuronal cells. We hypothesized that Pr P C expression levels may regulate EGFR signaling and that detailed understanding of this signaling pathway may enable identification of resistance mechanisms and new actionable targets in colorectal cancer. We performed molecular pathway analysis following knockdown of Pr P C or inhibition of EGFR signaling via gefitinib to identify changes in expression of key signaling proteins that determine cellular sensitivity or resistance to cisplatin. Expression of these proteins was examined in matched primary and metastatic patient samples and was correlated for resistance to therapy and progression of disease. Utilizing three colorectal cancer cell lines, we observed a correlation between high expression of Pr P C and resistance to cisplatin. Investigation of molecular signaling in a resistant cell line revealed that Pr P C contributed to signaling via colocalization with EGFR , which could be overcome by targeting p38 mitogen‐activated protein kinases (p38 MAPK ). We revealed that the level of Krüppel‐like factor 5 ( KLF 5), a target downstream of p38 MAPK , was predictive for cell line and patient response to platinum agents. Further, high KLF 5 expression was observed in BRAF ‐mutant colorectal cancer. Our study indicates that the EGFR to KLF 5 pathway is predictive of patient progression on platinum‐based therapy.

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Krüppel-Like Factor 5 Mediates Cellular Transformation During Oncogenic KRAS-Induced Intestinal Tumorigenesis

Abstract: Background & Aims-Krüppel-like factor 5 (KLF5) is a zinc finger-containing transcription factor that regulates cell proliferation. Oncogenic KRAS mutations are commonly found in colorectal cancers. We aimed to determine whether KLF5 mediates KRAS functions during intestinal tumorigenesis.

Cited by 115 publications

References 38 publications

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

Identifying Diagnostic MicroRNAs and Investigating Their Biological Implications in Rectal Cancer

EGFR and Prion protein promote signaling via FOXO3a‐KLF5 resulting in clinical resistance to platinum agents in colorectal cancer

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