Dickkopf-1 inhibits thyroid cancer cell survival and migration by regulating  -catenin/E-cadherin signaling Sun Wook Cho, Eun Jung Lee, Young A Kim, Kyung.

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Dickkopf-1 inhibits thyroid cancer cell survival and migration by regulating  -catenin/E-cadherin signaling Sun Wook Cho, Eun Jung Lee, Young A Kim, Kyung Won Kim, Jung Ah Lim, Won Sang Yoo, Hoon Sung Choi, Hwa Young Ahn, Ka Hee Yi, Do Joon Park, Bo Youn Cho, Young Joo Park Department of Internal Medicine, Seoul National University College of Medicine Department of Pathology, Seoul National University Boramae Medical Center Department of Internal Medicine, Seoul National University Boramae Medical Center Department of Internal Medicine, Chung-Ang University Hospital

Wnt/  -catenin/E-cadherin signaling in oncogenesis

Role of Dkk-1 in oncogenesis in human cancers Pancreatic cancer 1 Esophageal cancer 2 NSCLC 2 Colon cancer 3 Hepatocellular carcinoma 4 ONCOGENE TUMOR SURPRESSOR GENE 1 Takahashi et al., Yamabuki et al., Kuphal et al., Qin et al., 2007

Tissue microarray ( , SNUH) PTC (n=150), ATC (n=15) PTC, membranous PTC, cytoplasmic PTC, nucleusATC, nuclear A subset of PTC patient showed aberrant expression of  -catenin 2009, Korean Endocrine Socitey

Aim of study To evaluate the associations between the expression of  -catenin and E-cadherin with clinical characteristics in human PTC. To investigate the therapeutic potential of Dkk-1 in human PTC in vitro and in vivo

Localization of  -catenin Normal membranous (n=135) Decreased Membranous (n=7) Cytoplasmic dominant (n=7) P-values E-cadherin P<0.001 Normal130 (98.5)1 (25.0)2 (20.0) Aberrant5 (1.5)6 (75.0)5 (80.0) Cyclin D1 P=0.003 Negative9 (6.7)4 (57.1)1 (14.3) Positive125 (93.3)3 (42.9)6 (85.7) The correlation between  -catenin and E-cadherin in human PTC Tissue microarray ( , SNUH), PTC (n=150)

Comparisons of clinical characteristics according to the  -catenin/E-cadherin status P-value E-cadherin P-value Membrane dominant All aberrant NormalLoss (n=134)(n=16)(n=133)(n=17) Age at diagnosed (mean ± SD) ± ± ± ± Female, n (%)22 (16.4)4 (25.0) (16.5)4 (23.5)0.489 Tumor size (cm)2.43 ± ± ± ± Extrathyroidal invasion, n (%) 96 (71.6)10 (62.5) (71.4)11 (64.7)0.572 LN metastasis, n (%) 64 (66.7)11 (78.6) (64.9)14 (87.5)0.054 Recurrence or metastasis, n (%) 8 (11.8)5 (45.5) (11.6)5 (50.0)0.007 Median follow-up duration: 14.4 (13  15 ) years  -catenin

hDKK-1 hGAPDH P<0.05 Dkk-1/GAPDH NormalCancer Dkk-1, as a tumor suppressor gene in human PTC H-tori B-CPAP BHP10-3 SNU790 Dkk-1/GAPDH hDKK-1 hGAPDH H-tori B-CPAP BHP10-3 SNU790 Human PTC tissueHuman PTC cell-lines NormalCancer

SNU-790     BHP10-3 Cyclin D1 SNU  790 B  CPAP  -actin Cleaved Caspase-3 Frequency Intensity of Annexin V VEHDkk-1 +Dkk-1 Dkk-1 inhibited tumor cell survivals in human PTC cells VEHDkk-1 SNU-790BHP10-3 Vehicle Dkk-1 (20nM)   Annexin V + Cell (%) +Dkk-1 BHP10-3SNU-790

Treatment of Dkk-1 rescue an aberrant expression of  -catenin SNU  790 BHP10  3 VehiclesDkk-1 Anti-  -catenin Ab NS Vehicle Dkk-1 NS

Na/K-ATPase GAPDH E-cadherin DKK-1 (nM) CytosolMembrane Treatment of Dkk-1 rescue the loss of E-cadherin expression Effects of Dkk-1 on E-cadherin expression VehiclesDkk-1 Anti-E-cadherin Ab

 Migration (%) Effects of Dkk-1 on cell migration VEHDkk-1 Vehicle Dkk-1 VehicleDkk-1 Invading cells Matrigel Matrigel invasion assay Dkk-1  Wound healing assay

Tumors from Xenotransplantation of BHP10-3 cells overexpressing Dkk    Control Dkk-1 pMSCV  IRES  GFP pMSCV  Dkk-1  IRES  GFP Retrovirus-mediated Dkk-1 overexpression in BHP10-3 cells Control Dkk-1 ControlDkk-1 Tumor volume (mm 3 )

 -catenin E-cadherin Control Dkk-1 Tumors from Xenotransplantation of BHP10-3 cells overexpressing Dkk-1 H&E

Summaries Loss of membranous E-cadherin expression was significantly correlated with aberrant locations of  -catenin. Patients with loss of E-cadherin expression and aberrant locations of  -catenin showed higher rates of LN or distant metastasis than those with normal membranous staining.

Summaries Dkk-1 treatment inhibited PTC cell survival and rescued the aberrant expression of  -catenin from cytoplasm to membrane. Dkk-1 also recovered the loss of membranous E-cadherin expression in PTC cells, inhibiting cell migration and invasion. Xenotransplantation of BHP10-3 cells overexpressing Dkk-1 showed delayed tumorigenesis with relocations of the aberrant expression of  -catenin and E-cadherin.

Conclusions Dkk-1 might have a therapeutic potential in PTC through regulation of  -catenin/E-cadherin system