title: High cytoplasmic expression of Krüppel-like factor 4 is an independent prognostic factor of better survival in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality in the world. Hepatocarcinogenesis is complex, with an extraordinary molecular heterogeneity. Krüppel-like factor 4 (KLF4) plays an important role in cell proliferation and differentiation, and it can function as a tumor suppressor or an oncoprotein, depending on tissue type. The role of KLF4 in HCC remains controversial. The aim of this study was to explore the clinical significance of KLF4 expression in HCC. The study included 205 patients with surgical resection. We performed immunostaining for KLF4 and Ki-67 to investigate the correlations of the clinicopathological parameters of HCC and to examine the proliferative index. KLF4 staining was observed in the cytoplasm of non-tumorous hepatocytes and tumor cells. We subdivided the immunohistological staining results for KLF4 into low expression (Staining 0 and 1+) and high expression (Staining 2+ and 3+) subgroups. The expression of KLF4 was significantly correlated with tumor differentiation (p = 0.001). The Ki-67 proliferative index was significantly lower in well-differentiated HCCs (0.781% ± 1.02% vs. 2.16% ± 3.14%, p = 0.012), but not significantly different between low-KLF4 expression and high-KLF4 expression (1.87% ± 2.93% vs. 2.51% ± 3.28%, p = 0.32). Kaplan-Meier analysis showed that a high expression of KLF4 was significantly correlated with a longer disease-specific survival (p = 0.019). Univariate and multivariate analyses showed that high KLF4 expression was an independent predictor of a better disease-specific survival (p = 0.017; hazard ratio = 0.398; 95% confidence interval: 0.19-0.85). High cytoplasmic expression of KLF4 was associated with better disease-specific survival and was an independently favorable prognostic factor in hepatocellular carcinoma. These promising results suggest that KLF4 may play an anti-oncogenic role in hepatocarcinogenesis.
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan. javawomanfanny@gmail.com.
authors.forename: Hui-Ting
authors.initials: HT
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan. peiruwu5@gmail.com.
authors.forename: Pei-Ru
authors.initials: PR
authors.lastname: Wu
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan. cjchen1016@gmail.com.
authors.forename: Chih-Jung
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 402, Taiwan. lsh316@csmu.edu.tw.
authors.forename: Li-Sung
authors.initials: LS
authors.lastname: Hsu
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan. 28935@cch.org.tw.
authors.forename: Chung-Min
authors.initials: CM
authors.lastname: Yeh
authors.affiliation: Department of Neurosurgery, Changhua Christian Hospital, Changhua 500, Taiwan. javafatmark@gmail.com.
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Hsing
authors.affiliation: Biobank, Changhua Christian Hospital, Changhua 500, Taiwan. 146688@cch.org.tw.
authors.forename: Yi-Shan
authors.initials: YS
authors.lastname: Chiang
authors.affiliation: Department of Pathology, Chung Shan Medical University, Taichung 500, Taiwan. mtlai@csmu.edu.tw.
authors.forename: Ming-Tsung
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua 500, Taiwan. 10159@cch.org.tw.
authors.forename: Kun-Tu
authors.initials: KT
authors.lastname: Yeh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000473:pathology; D049109:Cell Proliferation; D003593:Cytoplasm / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000032:analysis*; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor; C000715467:KLF4 protein, human; D019394:Ki-67 Antigen; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors