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Thongchot, Suyanee,Yongvanit, Puangrat,Loilome, Watcharin,Seubwai, Wanchana,Phunicom, Kutcharin,Tassaneeyakul, Wichittra,Pairojkul, Chawalit,Promkotra, Wisuttiphong,Techasen, Anchalee,Namwat, Nisana Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.14
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-$1{\alpha}$ 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 ($CoCl_2$ treatment) was also tested regarding CCA cell functions. Our results showed that HIF-$1{\alpha}$ (66%), BNIP3 (44%) and PI3KC3 (46%) showed strong staining in human CCA tissues. Positive expression of HIF-$1{\alpha}$ (p=0.033), BNIP3 (p=0.040) and PI3KC3 (p=0.037) was significantly correlated with lymph node metastasis. HIF-$1{\alpha}$ 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-$1{\alpha}$ (p=0.047) or co-expressed HIF-$1{\alpha}$ and BNIP3 (p=0.032) or HIF-$1{\alpha}$ and PI3KC3 (p=0.043) were significantly greater than in the negative groups. CCA cells treated with $CoCl_2$ showed an increase in HIF-$1{\alpha}$, 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.
Chloroquine Exerts Anti-metastatic Activities Under Hypoxic Conditions in Cholangiocarcinoma Cells
Thongchot, Suyanee,Loilome, Watcharin,Yongvanit, Puangrat,Dokduang, Hasaya,Thanan, Raynoo,Techasen, Anchalee,Namwat, Nisana Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5
Intra-tumoral hypoxia is an environment that promotes tumor cell migration, angiogenesis and epithelial-mesenchymal transition that accounts for a major mechanism of metastasis. Chloroquine potentially offers a new therapeutic approach with an 'old' drug for effective and safe cancer therapies, as it exerts anti-metastatic activity. We investigated the inhibitory effect of chloroquine on cholangiocarcinoma (CCA) cell migration under cobalt chloride ($CoCl_2$)-stimulated hypoxia. We showed that chloroquine suppressed CCA cell migration under hypoxic-mimicking conditions on exposure to $100{\mu}M$ $CoCl_2$. Moreover, chloroquine stabilized the protein level of prolyl hydroxylase domain proteins (PHD-2) but reduced the levels of hypoxic responsive proteins such as hypoxia-inducible factor (HIF-$1{\alpha}$) and vascular endothelial growth factor (VEGF). It also suppressed epithelial mesenchymal transition (EMT) by increasing the ratio of E-cadherin to N-cadherin under hypoxic conditions. In conclusion, chloroquine can inhibit hypoxia-stimulated metastasis via HIF-$1{\alpha}$/VEGF/EMT which may serve as a useful additional strategy for CCA therapy.
Yothaisong, Supak,Thanee, Malinee,Namwat, Nisana,Yongvanit, Puangrat,Boonmars, Thidarut,Puapairoj, Anucha,Loilome, Watcharin Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23
Opisthorchis viverrini (Ov) infection is the major etiological factor for cholangiocarcinoma (CCA), especially in northeast Thailand. We have previously reported significant involvement of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin in human CCA tissues. The present study, therefore, examined the expression and activation of PI3K/AKT/PTEN and $Wnt/{\beta}$-catenin signaling components during Ov-induced cholangiocarcinogenesis in a hamster animal model. Hamsters were divided into two groups; non-treated and Ov plus NDMA treated. The results of immunohistochemical staining showed an upregulation of PI3K/AKT signaling as determined by elevated expression of the $p85{\alpha}$-regulatory and $p110{\alpha}$-catalytic subunits of PI3K as well as increased expression and activation of AKT during cholangiocarcinogenesis. Interestingly, the staining intensity of activated AKT (p-AKT) increased in the apical regions of the bile ducts and strong staining was detected where the liver fluke resides. Moreover, PTEN, a negative regulator of PI3K/AKT, was suppressed by decreased expression and increased phosphorylation during cholangiocarcinogenesis. We also detected upregulation of $Wnt/{\beta}$-catenin signaling as determined by increased positive staining of Wnt3, Wnt3a, Wnt5a, Wnt7b and ${\beta}$-catenin, corresponded with the period of cholangiocarcinogenesis. Furthermore, nuclear staining of ${\beta}$-catenin was observed in CCA tissues. Our results suggest the liver fluke infection causes chronic inflammatory conditions which lead to upregulation of the PI3K/AKT and $Wnt/{\beta}$-catenin signaling pathways which may drive CCA carcinogenesis. These results provide useful information for drug development, prevention and treatment of CCA.
Chaisiri Wongkham,Arthit Tolek,Nittaya Chamadol,Puangrat Yongvanit,Sopit Wongkham 한국당과학회 2012 한국당과학회 학술대회 Vol.2012 No.1
The incidence of cholangiocarcinoma (CCA), a bile duct cancer, is high in the northeastern part of Thailand. At present, there is no known marker that can be used as an early marker for CCA. The surveillance of people at risk of CCA is the effective strategy to detect patients with early CCA, the stage at which surgery for completely cure can be offered. There is accumulated evidence indicated that people with chronic inflammation of bile duct epithelia and peribiliary fibrosis have high risk of CCA. Recently, a high resolution ultrasonography of peri-portal fibrosis was shown to be the acceptable approach to identify people at high risk or early CCA. However, the ultrasonography has to be conducted and determined by an experience radiologist and the operation cannot be offered for people in rural area. In this study, we aimed to find a suitable serum marker that can distinguish people who has benign bilirary diseases (BBD) or CCA from healthy subjects, liver fluke infected persons and patients with other gastro-intestinal cancers. Serum was electrophoresesed in a 12% SDS-polyacrylamide gel electrophoresis and ConA-binding glycoproteins were determined using lectin-biotin/avidin-peroxidase system. ConA blotting of serum from 29 CCA and 23 benign biliary diseases were compared with those from healthy persons (n = 20), active liver fluke infected people (n =10), patients with hepatoma (n =15) and other gastro-intestinal cancers (n =20). A high molecular weight of ConA binding glycoprotein was frequently detected in 85% of serum from CCA and BBD comparing to 24.6% of all serum from the control group. This marker can identify person who had CCA or BBD with a 81.6% sensitivity, 75.4% specificity, 73.3% and 85.9% positive and negative predictive values, respectively. The value of this ConA-specific marker in differentiating people who are at risk of CCA should be re-investigated in a larger cohort including people from the villages that are in the endemic area of liver fluke infection and patients with various pathological conditions.
Thanee, Malinee,Loilome, Watcharin,Techasen, Anchalee,Namwat, Nisana,Boonmars, Thidarut,Pairojkul, Chawalit,Yongvanit, Puangrat Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.7
The tumor microenvironment (TME) includes numerous non-neoplastic cells such as leukocytes and fibroblasts that surround the neoplasm and influence its growth. Tumor-associated macrophages (TAMs) and cancerassociated fibroblasts (CAFs) are documented as key players in facilitating cancer appearance and progression. Alteration of the macrophage (CD68, CD163) and fibroblast (${\alpha}-SMA$, FSP-1) cells in Opisthorchis viverrini (Ov) -induced cholangiocarcinoma (CCA) was here assessed using liver tissues from an established hamster model and from 43 human cases using immunohistochemistry. We further investigated whether M2-activated TAMs influence CCA cell migration ability by wound healing assay and Western blot analysis. Macrophages and fibroblasts change their phenotypes to M2-TAMs (CD68+, CD163+) and CAFs (${\alpha}-SMA+$, FSP-1+), respectively in the early stages of carcinogenesis. Interestingly, a high density of the M2-TAMs CCA in patients is significantly associated with the presence of extrahepatic metastases (p=0.021). Similarly, CD163+ CCA cells are correlated with metastases (p=0.002), and they may be representative of an epithelial-to-mesenchymal transition (EMT) with increased metastatic activity. We further showed that M2-TAM conditioned medium can induce CCA cell migration as well as increase N-cadherin expression (mesenchymal marker). The present work revealed that significant TME changes occur at an early stage of Ov-induced carcinogenesis and that M2-TAMs are key factors contributing to CCA metastasis, possibly via EMT processes.
Khenjanta, Chakkaphan,Thanan, Raynoo,Jusakul, Apinya,Techasen, Anchalee,Jamnongkan, Wassana,Namwat, Nisana,Loilome, Watcharin,Pairojkul, Chawalit,Yongvanit, Puangrat Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.23
Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2) in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker, was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally, immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.