title: High expression of HIF-1α, BNIP3 and PI3KC3: hypoxia-induced autophagy predicts cholangiocarcinoma survival and metastasis.
abstract: Hypoxia and autophagy are known to facilitate tumor progression. We here aimed to investigate the role of hypoxia-associated autophagy in cholangiocarcinoma (CCA) survival and metastasis. Immunostaining of hypoxic- responsive proteins (HIF-1α and BNIP3) and a key regulator of autophagy (PI3KC3) were examined in CCA tissues and their expression levels were compared with clinicopathological parameters. A hypoxia mimicking condition (CoCl2 treatment) was also tested regarding CCA cell functions. Our results showed that HIF-1α (66%), BNIP3 (44%) and PI3KC3 (46%) showed strong staining in human CCA tissues. Positive expression of HIF-1α (p=0.033), BNIP3 (p=0.040) and PI3KC3 (p=0.037) was significantly correlated with lymph node metastasis. HIF-1α was well associated with BNIP3 (r=0.3, p<0.01) and PI3KC3 (r=0.2, p<0.01). The survival rates of patients who were positive with HIF-1α (p=0.047) or co-expressed HIF-1α and BNIP3 (p=0.032) or HIF-1α and PI3KC3 (p=0.043) were significantly greater than in the negative groups. CCA cells treated with CoCl2 showed an increase in HIF-1α, BNIP3, PI3KC3 and LC3-II, with increased cell migration and pFAK levels. These data suggest that hypoxia associated autophagy enhances CCA metastasis, resulting in a poor prognosis of CCA.
authors: Departments of 1Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand E-mail : nisana@kku.ac.th.
authors: Suyanee
authors: S
authors: Thongchot
authors: Puangrat
authors: P
authors: Yongvanit
authors: Watcharin
authors: W
authors: Loilome
authors: Wanchana
authors: W
authors: Seubwai
authors: Kutcharin
authors: K
authors: Phunicom
authors: Wichittra
authors: W
authors: Tassaneeyakul
authors: Chawalit
authors: C
authors: Pairojkul
authors: Wisuttiphong
authors: W
authors: Promkotra
authors: Anchalee
authors: A
authors: Techasen
authors: Nisana
authors: N
authors: Namwat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy; D001650:Bile Duct Neoplasms / Q000401:mortality / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D018281:Cholangiocarcinoma / Q000401:mortality / Q000473:pathology*; D003035:Cobalt / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis*; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*
chemical_list: C090121:BNIP3 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D003035:Cobalt; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C018021:cobaltous chloride