Characterization of a candidate tumor suppressor gene uroplakin 1A in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is increasing in incidence, but the knowledge of the genetic underpinnings of this disease remains limited. In this study, we identified the tetraspanin cell surface receptor uroplakin 1A (UPK1A) as a candidate tumor suppressor gene (TSG), and we investigated its function and mechanism in ESCC cells. UPK1A downregulation occurred in 68% of primary ESCCs examined, where it was correlated significantly with promoter hypermethylation (P < 0.05). Ectopic expression of UPK1A in ESCC cells inhibited cell proliferation, clonogenicity, cell motility, and tumor formation in nude mice. Mechanistic investigations suggested that these effects may be mediated by inhibiting nuclear translocation of β-catenin and inactivation of its downstream targets, including cyclin-D1, c-jun, c-myc, and matrix metalloproteinase 7 (MMP7). Cell cycle arrest elicited by UPK1A at the G(1)-S checkpoint was associated with downregulation of cyclin D1 and cyclin-dependent kinase 4, whereas metastasis suppression was associated with reduction of MMP7. These findings were consistent with evidence derived from clinical samples, where UPK1A downregulation was correlated with lymph node metastasis (P = 0.009), stage (P = 0.015), and overall survival (P < 0.0001). Indeed, multivariate cyclooxygenase regression analysis showed that UPK1A was an independent prognostic factor for overall survival. Taken together, our findings define a function for UPK1A as an important TSG in ESCC development.
Kong
Kar Lok
KL
Department of Clinical Oncology and Center for Cancer Research and Department of Surgery, University of Hong Kong, Pokfulam, Hong Kong.
Kwong
Dora L
DL
Fu
Li
L
Chan
Tim Hon Man
TH
Chen
Leilei
L
Liu
Haibo
H
Li
Yan
Y
Zhu
Ying-Hui
YH
Bi
Jiong
J
Qin
Yan-Ru
YR
Law
Simon Ying Kit
SY
Guan
Xin-Yuan
XY
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D060167:Uroplakin Ia; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C086451:UPK1A protein, human; D060167:Uroplakin Ia