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Clinicopathological Significance of Osteopontin in Cholangiocarcinoma Cases
Laohaviroj, Marut,Chamgramol, Yaovalux,Pairojkul, Chawalit,Mulvenna, Jason,Sripa, Banchob Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.1
Cholangiocarcinoma (CCA) is generally a rare primary liver tumor of the bile duct with extremely poor clinical outcomes due to late diagnosis. Osteopontin (OPN) is the most abundant expressed gene in intrahepatic CCA and its involvement in tumor aggressiveness suggests it could be a useful prognostic biomarker. However, the prognostic significance of OPN expression in CCA is still controversial. We therefore immunohistochemically studied OPN expression in 354 resected CCAs and correlated the results with patient clinicopathological parameters. OPN expression was separately scored according to the percentage of cancer cells or degree of stromal tissue staining and classified as low (score 0-1) and high (score 2-3). OPN expression in CCA cells was found in 177 out of 354 patients (56.5%), whereas stroma was positive in 185 out of 354 patients (52.3%). Univariate analysis with several of the aforementioned parameters revealed that stromal but not cancer cell OPN expression was significantly associated with tumor size, tumor direct invasion into normal liver parenchyma, regional lymph node metastasis and higher staging. The combination of cancer cell and stromal OPN expression demonstrated a positive trend for linkage with lymph node metastasis. Multivariate analysis identified gender, the presence of lymphatic permeation and lymph node metastasis, but not OPN expression, as independent prognostic factors. This study confirms the presence of stromal OPN expression in tumor aggressiveness but not survival in CCA patients.
Prayong, Pokpong,Mairiang, Eimorn,Pairojkul, Chawalit,Chamgramol, Yaovalux,Mairiang, Pisaln,Bhudisawasdi, Vajarabhongsa,Sripa, Banchob Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.13
The cholangiocarcinoma (CCA) is a relatively rare cancer worldwide but it is highly prevalent in Thailand where the liver fluke, Opisthorchis viverrini is endemic. There are reports that interleukin 6 (IL-6) may play an important role in the pathogenesis of opisthorchiasis associated CCA. Functionally, IL-6 can act on target cells through its receptor, IL-6R, and IL-6R polymorphisms may affect the functional activity of IL-6 leading to susceptibility to cholangiocarcinogenesis. Therefore, we assessed the association of the 48892 A/C (Asp358Ala) polymorphism in exon 9 of the IL-6R gene in 79 CCA cases compared to 80 healthy controls using the PCR-RFLP technique. The results showed significant differences between CCA cases and controls in overall genotype (p=0.001) and allele frequencies (p=0.0002). Chi-square for trend test revealed a significant association between genotype and CCA susceptibility (p=0.0002). The odds ratios (ORs) for genotype were 0.283 (95% CI=0.131-0.605, AC vs. AA; p=0.0003) and 0.206 (95% CI=0.196-1.245, CC vs. AA; p=0.0416), the OR for alleles was 0.347 (95% CI=0.187-0.633, allele C vs. allele A; p=0.0002) and that for the carrier C variant was 0.272 (95% CI=0.130-0.564; p=0.0001). This study demonstrated a close association between an IL-6R polymorphism, specifically higher A allele, and cholangiocarcinoma.
The Carcinogenic Liver Fluke Opisthorchis viverrini is a Reservoir for Species of Helicobacter
Deenonpoe, Raksawan,Chomvarin, Chariya,Pairojkul, Chawalit,Chamgramol, Yaowalux,Loukas, Alex,Brindley, Paul J,Sripa, Banchob Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5
There has been a strong, positive correlation between opisthorchiasis-associated cholangiocarcinoma and infection with Helicobacter. Here a rodent model of human infection with Opisthorchis viverrini was utilized to further investigate relationships of apparent co-infections with O. viverrini and H. pylori. A total of 150 hamsters were assigned to five groups: i) Control hamsters not infected with O. viverrini; ii) O. viverrini-infected hamsters; iii) non-O. viverrini infected hamsters treated with antibiotics (ABx); iv) O. viverrini-infected hamsters treated with ABx; and v) O. viverrini-infected hamsters treated both with ABx and praziquantel (PZQ). Stomach, gallbladder, liver, colonic tissue, colorectal feces and O. viverrini worms were collected and the presence of species of Helicobacter determined by PCR-based approaches. In addition, O. viverrini worms were cultured in vitro with and without ABx for four weeks, after which the presence of Helicobacter spp. was determined. In situ localization of H. pylori and Helicobacter-like species was performed using a combination of histochemistry and immunohistochemistry. The prevalence of H. pylori infection in O. viverrini-infected hamsters was significantly higher than that of O. viverrini-uninfected hamsters ($p{\leq}0.001$). Interestingly, O. viverrini-infected hamsters treated with ABx and PZQ (to remove the flukes) had a significantly lower frequency of H. pylori than either O. viverr-iniinfected hamsters treated only with ABx or O. viverrini-infected hamsters, respectively ($p{\leq}0.001$). Quantitative RT-PCR strongly confirmed the correlation between intensity H. pylori infection and the presence of liver fluke infection. In vitro, H. pylori could be detected in the O. viverrini worms cultured with ABx over four weeks. In situ localization revealed H. pylori and other Helicobacter-like bacteria in worm gut. The findings indicate that the liver fluke O. viverrini in the biliary tree of the hamsters harbors H. pylori and Helicobacter-like bacteria. Accordingly, the association between O. viverrini and H. pylori may be an obligatory mutualism.
Gene Expression Profiling of Intrahepatic Cholangiocarcinoma
Subrungruang, Ittisak,Thawornkuno, Charin,Chawalitchewinkoon-Petmitr, Porntip,Pairojkul, Chawalit,Wongkham, Sopit,Petmitr, Songsak Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.1
Intrahepatic cholangiocarcinoma (ICC) is ranked as one of the top five causes of cancer-related deaths. ICC in Thai patients is associated with infection with the liver fluke, Opisthorchis viverrini, but the molecular basis for development remains unclear. The present study employed a microarray approach to compare gene expression profiles of ICCs and normal liver tissues from the same patients residing in Northeast Thailand, a region with a high prevalence of liver fluke infection. In ICC samples, 2,821 and 1,361 genes were found to be significantly up- and down-regulated respectively (unpaired t-test, p<0.05; fold-change ${\gep}2.0$). For validation of the microarray results, 7 up-regulated genes (FXYD3, GPRC5A, CEACAM5, MUC13, EPCAM, TMC5, and EHF) and 3 down-regulated genes (CPS1, TAT, and ITIH1) were selected for confirmation using quantitative RT-PCR, resulting in 100% agreement. The metallothionine heavy metal pathway contains the highest percentage of genes with statistically significant changes in expression. This study provides exon-level expression profiles in ICC that should be fruitful in identifying novel genetic markers for classifying and possibly early diagnosis of this highly fatal type of cholangiocarcinoma.
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.
Patterns of Recurrence after Resection of Mass-Forming Type Intrahepatic Cholangiocarcinomas
Luvira, Vor,Eurboonyanun, Chalerm,Bhudhisawasdi, Vajarabhongsa,Pugkhem, Ake,Pairojkul, Chawalit,Luvira, Varisara,Sathitkarnmanee, Egapong,Somsap, Kulyada,Kamsa-ard, Supot Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.10
Background: Intrahepatic cholangiocarcinoma (IHCCA) is an aggressive tumor for which surgical resection is a mainstay of treatment. However, recurrence after resection is common associated with a poor prognosis. Studies regarding recurrence of mass-forming IHCCA are rare; therefore, we investigated the pattern with our dataset. Methods: We retrospectively reviewed the medical and pathological records of 50 mass-forming IHCCA patients who underwent hepatic resection between January 2004 and December 2009 in order to determine the patterns of recurrence and prognosis. All demographic and operative parameters were analyzed for their effects on recurrence-free survival. Results: The median recurrence-free survival time was 188 days (95%CI: 149-299). The respective 1-, 2-, and 3-year recurrence-free survival rates were 16.2% (95%CI: 6.6-29.4), 5.4% (95%CI: 1.0-15.8) and 2.7% (95%CI: 0.2-12.0). There was an equal distribution of recurrence at solitary and multiple sites. Univariate analysis revealed no factors related to recurrence-free survival.Conclusion: The overall survival and recurrence-free survival after surgery for mass-forming IHCCA were found to be very poor. Almost all recurrences were detected within 2 years after surgery. Adjuvant chemotherapy after surgery may add benefit in the affected patients.
Muisuk, Kanha,Silsirivanit, Atit,Imtawil, Kanokwan,Bunthot, Suphawadee,Pukhem, Ake,Pairojkul, Chawalit,Wongkham, Sopit,Wongkham, Chaisiri Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.5
Background: Mitochondrial DNA (mtDNA) mutations have been shown to be associated with cancer. This study explored whether mtDNA mutations enhance cholangiocarcinoma (CCA) development in individuals. Materials and Methods: The whole mitochondrial genome sequences of 25 CCA patient tissues were determined and compared to those of white blood cells from the corresponding individuals and 12 healthy controls. The mitochondrial genome was amplified using primers from Mitoseq and compared with the Cambridge Reference Sequence. Results: A total of 161 mutations were identified in CCA tissues and the corresponding white blood cells, indicating germline origins. Sixty-five (40%) were new. Nine mutations, representing those most frequently observed in CCA were tested on the larger cohort of 60 CCA patients and 55 controls. Similar occurrence frequencies were observed in both groups. Conclusions: While the correspondence between the cancer and mitochondrial genome mutation was low, it is of interest to explore the functions of the missense mutations in a larger cohort, given the possibility of targeting mitochondria for cancer markers and therapy in the future.
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.