Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Yothaisong, Supak; Thanee, Malinee; Namwat, Nisana; Yongvanit, Puangrat; Boonmars, Thidarut; Puapairoj, Anucha; Loilome, Watcharin

doi:10.7314/apjcp.2014.15.23.10463

Cited by 40 publications

(31 citation statements)

References 26 publications

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“…Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis. Total mRNA was isolated from 4x10 6 HuCCA-1 cells using an RNA purification cell kit (5 PRIME GmbH, Hamburg, Germany) according to the manufacturer's recommendations. Contaminating DNA was removed using the Turbo DNA-free™ DNase kit (Applied Biosystems; Thermo Fisher Scientific, Inc.).…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have reported the involvement of phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in CCA. It has been shown that the expression and activation of AKT protein increase during the development and progression of CCA (5,6), and that AKT is a promising target for CCA treatment (7). In addition, an activated PI3K/AKT signaling pathway is frequently found in CCA cells resistant to chemotherapy (8).…”

Section: Introductionmentioning

confidence: 99%

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Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

et al. 2018

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Cholangiocarcinoma (CCA) is a malignant tumor of the biliary epithelium associated with Opisthorchis viverrini, primary sclerosing cholangitis and hepatitis viral infection. In the global population, men have higher incidence rates for CCA than women; thus, a gender disparity in the progression of chronic inflammation of the biliary duct leading to malignancy may involve the effects of estrogen (E2). Genistein (GE), a prominent phytoestrogen found in soy products, is an estrogen receptor β (ERβ) agonist and a tyrosine kinase inhibitor. The present study investigated the effects of GE on the growth of CCA cells by cell viability assay. The effects on signaling proteins were detected by western blot analysis and ELISA. Gene expression was examined by RT-qPCR. Two human intrahepatic CCA cell lines, HuCCA‑1 and RMCCA‑1, were utilized. GE (50‑200 µM) reduced the viability of the two cell lines, and also inhibited the activation of epidermal growth factor receptor (EGFR) and AKT, as evidenced by decreasing protein levels of phosphorylated (p)-EGFR (Tyr1173) and p‑AKT (Ser473), respectively. GE altered the mitogen‑activated protein kinase signaling cascade by mediating decreased protein levels of p‑p38 and increased protein levels of p‑ERK1/2. GE significantly decreased the levels of interleukin 6 (IL6) and induced the expression of inducible nitric oxide synthase (iNOS). GE also downregulated the expression of p‑ERα (Ser118) protein and ERα mRNA levels. Finally, GE induced the downregulation of the protein levels of ERβ. Of note, E2 deprivation potentiated the GE-induced reduction of p‑EGFR (Tyr1173) and total AKT proteins and production of IL6, and mediated the downregulation of GE-induced iNOS protein. In conclusion, GE inhibited the growth of human CCA cell lines by reducing the activation of EGFR and AKT, and by attenuating the production of IL6. E2 and ER were also involved in the growth-inhibitory effect of GE in CCA cells.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

et al. 2018

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“…These proteins are members of the retinoblastoma protein (RB) pathway, which is strongly involved in cancer development. Moreover, the chronic inflammatory condition caused by O. viverrini leads to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways involved in tumorgenesis (Yothaisong et al, 2014). Recently, a proteomic study has indicated that the 14-3-3 eta protein is up-regulated during O. viverrini infection and in early stages of O. viverrini -induced cholangiocarcinoma (Haonon et al, 2015) and in intrahepatic cholangiocarcinoma of patients void of O. viverrini infection (Zhang et al, 2015), indicating that the 14-3-3 eta protein is involved in host responses and contributes to carcinogenesis.…”

Section: Liver Fluke Infections and Cholangiocarcinomamentioning

confidence: 99%

Parasite Infection, Carcinogenesis and Human Malignancy

et al. 2017

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Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity.

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“…Suppression of Wnt/β-catenin pathway signaling negatively impacts development of CCA (44). Moreover, apoptosis, growth, cellular intercommunication, and angiogenesis of CCA cells related with receptor tyrosine kinase (RTK) signaling that revealed the multiple kinases associated with PI3K/AKT, Wnt/β-catenin, MAPK, and/or JAK/STAT signaling pathways (45)(46)(47). In addition, GRN development affects the activation of the MAPK signaling pathway (48), highlighted by its upregulated of PGRN during hepatocellular carcinoma and as the gene target of microRNA-140-3p (miR-140-3p).…”

Section: Discussionmentioning

confidence: 99%

Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma

Arunsan

Chaidee

et al. 2019

Preprint

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Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with fish-borne liver flukes is a major risk factor for cholangiocarcinoma (CCA). The parasite secretes a growth factor termed liver fluke granulin (Ov-GRN-1), a homologue of the human progranulin (huPGRN), which contributes significantly to biliary tract fibrosis and morbidity during infection. Here, exosome-mediated transfer of mRNAs from the human cholangiocyte cell line (H69) was investigated following exposure to Ov-GRN-1, to naïve recipient H69 cells. To minimize the influence of endogenous huPGRN, the gene encoding huPGRN was inactivated using CRISPR/Cas9-based gene knock-out. Several huPGRN-depleted cell lines, termed DhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of huPGRN transcripts and protein, both in gene-edited cells and within exosomes released by these cells. Profiles of exosomal RNAs (exRNA) from DhuPGRN-H69 for CCAassociated characteristics revealed a paucity of transcripts for estrogen-and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific mRNAs including MAPK/AKT pathway members were induced by exposure to Ov-GRN-1. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 exposed to Ov-GRN-1. Of these, CCA-associated exRNAs modified the CCA microenvironment in naïve recipient cells co-cultured with exosomes from DhuPGRN-H69 exposed to Ov-GRN-1, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells comparing with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCAconducive disposition.

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Opisthorchis viverrini Infection Activates the PI3K/AKT/PTEN and Wnt/β-catenin Signaling Pathways in a Cholangiocarcinogenesis Model

Cited by 40 publications

References 26 publications

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

Genistein reduces the activation of AKT and EGFR, and the production of IL6 in cholangiocarcinoma cells involving estrogen and estrogen receptors

Parasite Infection, Carcinogenesis and Human Malignancy

Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma

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