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Dickkopf-1 Is the Potential Therapeutic Marker for Sorafenib Response in Hepatocellular Carcinoma
( Bora Jin ),( Seung Up Kim ),( Beom Kyung Kim ),( Jun Yong Park ),( Do Young Kim ),( Kwang-hyub Han ),( Sang Hoon Ahn ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1
Aims: Sorafenib, the multi-kinase inhibitor, is the only standard 1<sup>st</sup> line targeted anti-cancer agent for advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) which is an antagonist of Wnt signaling has been known to be overexpressed in HCC tumors and serum of patients with HCC. In this study, we aimed to investigate whether DKK1 is a sorafenib therapeutic biomarker and to clarify whether DKK1 is a good therapeutic target. Methods: Five Human HCC cell lines (Hep3B, HepG2, Huh7, SNU-449 and SNU-475) with different DKK1 expression were used in this study. Cell viability and proliferation level were determined by MTT assay. Expression of DKK1 after sorafenib treatment was analyzed by qRT-PCR, western blot and ELISA. To compare with clinical data, tissues and serum from patients with HCC treated sorafenib were collected and DKK1 level was analyzed using ELISA and qRT-PCR. Results: The viability and proliferation of the sorafenib treated cells was decreased. Among them, Hep3B, which secretes the greatest amount of DKK1, showed the highest resistance.mRNA level of DKK1 estimated by qRT-PCR was displayed down regulation in all sorafenib-treated HCC cell lines. In addition, the sorafenib altered expression level of secreted DKK1 in Hep3B and HepG2 and these were confirmed by ELISA and western blot. Taken together, our results showed that Sorafenib inhibits DKK1 expression in a dose-dependent manner. Next, to identify on human sample, we investigated that DKK1 level in patients’ sera using ELISA. As a results, DKK1 levels were lower in treated patients andthe expression level of DKK1 in HCC patients’ tissue was significantly reduced after liver section or treatment for HCC. Conclusions: We found that sorafenib down-regulated DKK1 expression in HCC cells and human samples. Our results indicate that DKK1 might be a useful serum biomarker for monitoring the therapeutic efficacy of sorafenib for HCC treatment.
Regulation of Tumor Angiogenesis and Endothelial Mesenchymal Transition by Dickkopf-1
( Sung Hoon Choi ),( Hyun Gyu Lee ),( Hyemi Kim ),( Jun Young Park ),( Beomkyung Kim ),( Do Young Kim ),( Sang Hoon Ahn ),( Kwang-hyub Han ),( Seung Up Kim ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: Tumor angiogenesis is essential for invasive tumor growth and metastasis. Dickkopf (DKK)-1, an antagonist of Wnt signal, participates in tumor development and progression. This study evaluated whether DKK-1 stimulation increases angiogenesis and endothelial mesenchymal transition. (EnMT) Methods: Human umbilical vein endothelial cells (HUVECs) were stimulated with recombinant DKK-1 or concentrated conditioned medium from human hepatoma cells or DKK-1-transfected 293 cells. Following stimulation, the expression levels of angiogenesis related factors and EnMT related markers were examined by immunoblot assays. In addition, the effect of exogenous DKK-1 on angiogenesis and EnMT were assessed by endothelial cell tube formation assay, cell invasion assay and wound healing assay. Results: Human hepatoma cells such as Hep3B and Huh-7 showed high expression levels of DKK-1, whereas 293 cells and HUVECs showed little or no expression. Increased endothelial cell tube formation and invasiveness were observed in HUVECs treated with either concentrated conditioned medium from DKK-1-overexpressed 293 cells, human hepatoma cells, or recombinant DKK-1. Increased cell motility was also shown in DKK-1-stimulated HUVECs in wound healing assay. Furthermore, the expression level of angiogenesis-related factors including vascular endothelial growth factor receptor 2 and vascular endothelial-cadherin was increased in DKK-1-stimulated HUVECs. In addition, the expression of EnMT markers such as vimentin and Twist was also increased in DKK-1-stimulated HUVECs. Conclusions: Our in vitro data suggest that DKK-1 enhances angiogenic and EnMT properties of HUVECs. Modulation of DKK-1 may shed light on development of novel strategies to control tumor angiogenesis and metastasis.
Increased Expression of Dickkopf-1 in Acral Lentiginous Melanoma
( Yoon Hyuk Choi ),( Seok Min Kim ),( Jun Young Kim ),( Man Hoon Han ),( Seok-jong Lee ) 대한피부과학회 2018 大韓皮膚科學會誌 Vol.56 No.4
Background: Dickkopf-1 (DKK-1), an inhibitor of the Wnt signaling pathway, is known as an inhibitor of melanocyte proliferation. In recent studies, the expression of DKK-1 gene is reduced in melanoma and they lose their preventive role during development or progression of melanoma. There are no available data regarding the changes in DKK-1 gene expression in acral lentiginous melanoma (ALM), which is common in Asians. Objective: To analyze changes in DKK-1 expression in the development or progression of ALM in Koreans. Methods: Immunohistochemical staining using DKK-1 antibody of 13 invasive ALM, six ALM in situ, nine acral nevi, and four benign non-related palmoplantar specimens as controls were evaluated by the semi-quantitative grading scale, which is divided into three distinctive grades according to the degree of cytoplasmic staining of DKK-1. Results: Among the invasive ALM specimens, seven of 13 (53.8%) were graded as strongly positive (2+), and only one case (7.7%) was negative. In cases of ALM in situ, two specimens (33.3%) stained positive (1+) and the remaining four specimens (66.6%) were not stained. All specimens from both acral nevus and benign palmoplantar lesions, which were used as the control group, were also negative. Conclusion: In contrast with recent reports, DKK-1 expression showed a positive correlation with ALM progression or invasiveness. The role of DKK-1 as a potential predictor of ALM progression warrants further study. (Korean J Dermatol 2018;56(4):259∼264)
( Liangbo Lin ),( Quanhe Qiu ),( Nian Zhou ),( Wen Dong ),( Jieliang Shen ),( Wei Jiang ),( Ji Fang ),( Jie Hao ),( Zhenming Hu ) 생화학분자생물학회 2016 BMB Reports Vol.49 No.3
Bone morphogenetic protein 9 (BMP9) is a potent inducer of osteogenic differentiation of mesenchymal stem cells. The Wnt antagonist Dickkopf-1 (Dkk1) is involved in skeletal development and bone remodeling. Here, we investigated the role of Dkk1 in BMP9-induced osteogenic differentiation of MSCs. We found that overexpression of BMP9 induced Dkk1 expression in a dose-dependent manner, which was reduced by the P38 inhibitor SB203580 but not the ERK inhibitor PD98059. Moreover, Dkk1 dramatically decreased not only BMP9-induced alkaline phosphatase (ALP) activity but also the expression of osteocalcin (OCN) and osteopontin (OPN) and matrix mineralization of C3H10T1/2 cells. Furthermore, exogenous Dkk1 expression inhibited Wnt/β-catenin signaling induced by BMP9. Our findings indicate that Dkk1 negatively regulates BMP9-induced osteogenic differentiation through inhibition of the Wnt/β-catenin pathway and it could be used to optimize the therapeutic use of BMP9 and for bone tissue engineering. [BMB Reports 2016; 49(3): 179-184]
( Moon Kyu Kim ),( Jung Chul Kim ),( Young Kwan Sung ),( Mi Hee Kwack ),( Ji Sup Ahn ) 생화학분자생물학회 2010 BMB Reports Vol.43 No.10
In a previous study, we recently claimed that dihydrotestoster-one (DHT)-inducible dickkopf-1 (DKK-1) expression is one of the key factors involved in androgen-potentiated balding. We also demonstrated that L-ascorbic acid 2-phosphate (Asc 2-P) represses DHT-induced DKK-1 expression in cultured dermal papilla cells (DPCs). Here, we investigated whether or not L-threonate could attenuate DHT-induced DKK-1 expression. We observed via RT-PCR analysis and enzyme-linked immunosorbent assay that DHT-induced DKK-1 expression was attenuated in the presence of L-threonate. We also found that DHT-induced activation of DKK-1 promoter activity was significantly repressed by L-threonate. Moreover, a co-culture system featuring outer root sheath (ORS) keratinocytes and DPCs showed that DHT inhibited the growth of ORS cells, which was then significantly reversed by L-threonate. Collectively, these results indicate that L-threonate inhibited DKK-1 expression in DPCs and therefore is a good treatment for the prevention of androgen-driven balding. [BMB reports 2010; 43 (10): 688-692]
Mi Hee Kwack,Sun Young Hwang,In Seok Jang,Sang Uk Im,김진오,김문규,김정철,Young Kwan Sung 대한암학회 2007 Cancer Research and Treatment Vol.39 No.1
Recent studies have shown that Dickkopf-1 (DKK-1) is overexpressed in some tumors, including hepatocellular carcinoma. However, the role of increased DKK-1 in these tumors is not known. In this study, the DKK-1 expression in hepatocellular carcinoma (HCC) cell lines was evaluated and the effect of DKK-1 overexpression in HCC cell lines was studied.Materials and Methods: The expression of DKK-1 in hepatocellular carcinoma cell lines was evaluated by RT-PCR. Stable cell lines that overexpressed DKK-1 were established. Cell growth, adhesion, migration and invasion assays were performed.Results: RT-PCR analysis showed that 5 out of 8 HCC cell lines expressed DKK-1. The forced expression of DKK-1 suppressed the growth of cells and increased the population of cells in the sub-G1 phase. In addition, DKK- 1 reduced the cellular adhesion capacity to collagen type I and fibronectin, and it increased migratory capacity. However, overexpression of DKK-1 did not increase the invasion capacity of the HCC cell line.Conclusion: Collectively, our data suggest that overexpression of DKK-1 affects the biology of HCC cells. (Cancer Res Treat. 2007;39:30-36)
Serum Dickkopf-1 as a Biomarker for the Diagnosis of Hepatocellular Carcinoma
김승업,박전한,한광협,김현숙,이재면,이현규,김혜미,최성훈,백신화,김범경,박준용,김도영,안상훈,이종두 연세대학교의과대학 2015 Yonsei medical journal Vol.56 No.5
Purpose: Dickkopf-1 (DKK-1) is a Wnt/β-catenin signaling pathway inhibitor. We investigated whether DKK-1 is related to progressionin hepatocellular carcinoma (HCC) cells and HCC patients. Materials and Methods: In vitro reverse-transcription polymerase chain reaction (RT-PCR), wound healing assays, invasion assays,and ELISAs of patient serum samples were employed. The diagnostic accuracy of the serum DKK-1 ELISA was assessed usingreceiver operating characteristic (ROC) curves and area under ROC (AUC) analyses. Results: RT-PCR showed high DKK-1 expression in Hep3B and low in 293 cells. Similarly, the secreted DKK-1 concentration in the culture media was high in Hep3B and low in 293 cells. Wound healing and invasion assays using 293, Huh7, and Hep3B cells showed that DKK-1 overexpression promoted cell migration and invasion, whereas DKK-1 knock-down inhibited them. When serum DKK-1 levels were assessed in 370 participants (217 with HCC and 153 without), it was significantly higher in HCC patients than in control groups (median 1.48 ng/mL vs. 0.90 ng/mL, p<0.001). The optimum DKK-1 cutoff level was 1.01 ng/mL (AUC=0.829; sensitivity 90.7%; specificity 62.0%). Although DKK-1 had a higher AUC than alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) (AUC=0.829 vs. 0.794 and 0.815, respectively), they were statistically similar (all p>0.05). When three biomarkerswere combined (DKK-1 plus AFP plus DCP), they showed significantly higher AUC (AUC=0.952) than single marker, DKK-1 plus AFP, or DKK-1 plus DCP (all p<0.001). Conclusion: DKK-1 might be a key regulator in HCC progression and a potential therapeutic target in HCC. Serum DKK-1 could complement the diagnostic accuracy of AFP and DCP.