title: PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis.
abstract: The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease.
authors: Department of Surgery, Nara Medical University, Kashihara, Nara, Japan.
authors: Ichiro
authors: I
authors: Yamato
authors: Masayuki
authors: M
authors: Sho
authors: Keiji
authors: K
authors: Shimada
authors: Kiyohiko
authors: K
authors: Hotta
authors: Yuko
authors: Y
authors: Ueda
authors: Satoshi
authors: S
authors: Yasuda
authors: Naoko
authors: N
authors: Shigi
authors: Noboru
authors: N
authors: Konishi
authors: Kazutake
authors: K
authors: Tsujikawa
authors: Yoshiyuki
authors: Y
authors: Nakajima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C505096:PCA-1 antigen, human; D034741:RNA, Small Interfering; D049308:Dioxygenases; C486439:ALKBH3 protein, human; D000071500:AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; D045643:DNA Repair Enzymes