Wen-Shih Huang1,2, Cheng-Yi Huang1, Meng-Chiao Hsieh1,3, Yi-Hung Kuo1,3, Shui-Yi Tung2,4, Chien-Heng Shen3,4, Yung-Yu Hsieh4, Chih-Chuan Teng5,6, Ko-Chao Lee7, Kam-Fai Lee8, Hsing-Chun Kuo5,6,9,10. 1. Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan. 2. Chang Gung University College of Medicine, Taoyuan, Taiwan. 3. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan. 4. Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Chiayi, Taiwan. 5. Institute of Nursing and Department of Nursing, Chang Gung Institute of Technology Chiayi Campus, Chiayi, Taiwan. 6. Research Fellow, Chang Gung Memorial Hospital, Chiayi, Taiwan. 7. Department of Colorectal Surgery, Department of Surgery, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Kaohsiung, Taiwan. 8. Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwanguscsi@gmail.com. 9. Chronic Diseases and Health Promotion Research Center, CGUST, Chiayi, Taiwan. 10. Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
Abstract
BACKGROUND/AIMS: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide. PRDXs are antioxidant enzymes that play an important role in cell differentiation, proliferation and apoptosis and have diverse functions in malignancy development. However, the mechanism of aberrant overexpression of PRDX6 in CRC remains unclear. METHODS: Boyden chamber assay, flow cytometry and a lentiviral shRNA targeting PRDX6 and transient transfection with pCMV-6-PRDX6 plasmid were used to examine the role of PRDX6 in the proliferation capacity and invasiveness of CRC cells. Immunohistochemistry (IHC) with tissue array containing 40 paraffin- embedded CRC tissue specimens and Western blot assays were used to detect target proteins. RESULTS: PRDX6 was significantly up-expressed in different comparisons of metastasis of colorectal adenomas in node-positive CRC (P = 0.03). In in vitro HCT-116, PRDX6 silencing markedly suppressed CRC cell migration and invasiveness while also inducing cell cycle arrest as well as the generation of reactive oxygen species (ROS); specific overexpression of PRDX6 had the opposite effect. Mechanistically, the PRDX6 inactivation displayed decreased levels of PRDX6, N-cadherin, β-catenin, Vimentin, Slug, Snail and Twist-1 through the activation of the PI3K/ AKT/p38/p50 pathways, but they were also significantly inhibited by PRDX6 transfectants. There was also increased transcriptional activation of dimethylation of histone H3 lysine 4 (H3K4me3) of PRDX6 promoter via the activation of the PI3K/Akt/NFkB pathways. CONCLUSION: Our findings demonstrated that PRDX6 expression plays a characteristic growth-promoting role in CRC metastasis. This study suggests that PRDX6 may serve as a biomarker of node-positive status and may have a role as an important endogenous regulator of cancer cell tumorigenicity in CRC. PRDX6 may also be an effective therapeutic target.
BACKGROUND/AIMS: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide. PRDXs are antioxidant enzymes that play an important role in cell differentiation, proliferation and apoptosis and have diverse functions in malignancy development. However, the mechanism of aberrant overexpression of PRDX6 in CRC remains unclear. METHODS: Boyden chamber assay, flow cytometry and a lentiviral shRNA targeting PRDX6 and transient transfection with pCMV-6-PRDX6 plasmid were used to examine the role of PRDX6 in the proliferation capacity and invasiveness of CRC cells. Immunohistochemistry (IHC) with tissue array containing 40 paraffin- embedded CRC tissue specimens and Western blot assays were used to detect target proteins. RESULTS:PRDX6 was significantly up-expressed in different comparisons of metastasis of colorectal adenomas in node-positive CRC (P = 0.03). In in vitro HCT-116, PRDX6 silencing markedly suppressed CRC cell migration and invasiveness while also inducing cell cycle arrest as well as the generation of reactive oxygen species (ROS); specific overexpression of PRDX6 had the opposite effect. Mechanistically, the PRDX6 inactivation displayed decreased levels of PRDX6, N-cadherin, β-catenin, Vimentin, Slug, Snail and Twist-1 through the activation of the PI3K/ AKT/p38/p50 pathways, but they were also significantly inhibited by PRDX6 transfectants. There was also increased transcriptional activation of dimethylation of histone H3lysine 4 (H3K4me3) of PRDX6 promoter via the activation of the PI3K/Akt/NFkB pathways. CONCLUSION: Our findings demonstrated that PRDX6 expression plays a characteristic growth-promoting role in CRC metastasis. This study suggests that PRDX6 may serve as a biomarker of node-positive status and may have a role as an important endogenous regulator of cancer cell tumorigenicity in CRC. PRDX6 may also be an effective therapeutic target.
Authors: María José López-Grueso; Daniel José Lagal; Álvaro Fernando García-Jiménez; Rosa María Tarradas; Beatriz Carmona-Hidalgo; José Peinado; Raquel Requejo-Aguilar; José Antonio Bárcena; Carmen Alicia Padilla Journal: Redox Biol Date: 2020-09-29 Impact factor: 11.799
Authors: Giuliana Cavalloni; Caterina Peraldo-Neia; Annamaria Massa; Carlo Bergamini; Alessandro Trentini; Giovanni De Rosa; Lorenzo Daniele; Fabiola Ciccosanti; Carlo Cervellati; Francesco Leone; Massimo Aglietta Journal: BMC Cancer Date: 2021-07-28 Impact factor: 4.430