Qi Li1, Yong Gao2, Zhiliang Jia3, Lopa Mishra4, Kun Guo3, Zhiwei Li5, Xiangdong Le3, Daoyan Wei3, Suyun Huang5, Keping Xie6. 1. Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2. Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. Electronic address: gaoyon@hotmail.com. 3. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4. Department of Gastroenterology and Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: kepxie@mdanderson.org.
Abstract
BACKGROUND & AIMS: Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling. METHODS: We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway. RESULTS: Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most human HCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastasis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D. CONCLUSIONS: KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.
BACKGROUND & AIMS: Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling. METHODS: We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway. RESULTS: Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most humanHCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastasis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D. CONCLUSIONS:KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.
Authors: Jennifer L Yori; Darcie D Seachrist; Emhonta Johnson; Kristen L Lozada; Fadi W Abdul-Karim; Lewis A Chodosh; William P Schiemann; Ruth A Keri Journal: Neoplasia Date: 2011-07 Impact factor: 5.715
Authors: K Dalhoff; J Dancey; L Astrup; T Skovsgaard; K J Hamberg; F J Lofts; O Rosmorduc; S Erlinger; J Bach Hansen; W P Steward; T Skov; F Burcharth; T R J Evans Journal: Br J Cancer Date: 2003-07-21 Impact factor: 7.640