NOTCH-YAP1/TEAD-DNMT1 axis regulates hepatocyte reprogramming into intrahepatic cholangiocarcinoma

ABSTRACTIntrahepatic cholangiocarcinoma (ICC), a disease of poor prognosis, has increased in incidence. It is challenging to treat due to intra- and inter-tumoral heterogeneity, which in part is attributed to diverse cellular origin. Indeed, co-expression of AKT and NICD in hepatocytes (HCs) yielded ICC, with similarity to proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD regulated SOX9 and YAP1 during ICC development. Yap1 deletion or TEAD inhibition impaired HC-to-biliary epithelial cell (BEC) reprogramming and ICC proliferation; Sox9 loss repressed tumor growth; and Yap1-Sox9 combined loss abolished ICC development in AKT-NICD model. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directed HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch-dependent HC-to-ICC development, and DNMT1 re-expression restored ICC development following TEAD repression. Coexpression of DNMT1 with AKT was sufficient to induce hepatic tumor development including ICC. Thus, we have identified a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for HC-driven ICC development.SIGNIFICANCEWe evaluated the clinical relevance of hepatocyte-driven ICC model and revealed critical but distinct roles of YAP1 and SOX9 in AKT-NICD-driven hepatocyte-derived ICC. We also identified NOTCH-YAP1/TEAD-DNMT1 axis as a critical driver for hepatocyte-to-ICC reprogramming, which might have biological and therapeutic implications in ICC subsets.

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MicroRNA Profiling of Human Intrahepatic Cholangiocarcinoma Cell Lines Reveals Biliary Epithelial Cell-specific MicroRNAs

Journal of Nippon Medical School ◽

10.1272/jnms.76.188 ◽

2009 ◽

Vol 76 (4) ◽

pp. 188-197 ◽

Cited By ~ 53

Author(s):

Yutaka Kawahigashi ◽

Takuya Mishima ◽

Yoshiaki Mizuguchi ◽

Yasuo Arima ◽

Shigeki Yokomuro ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Lines ◽

Intrahepatic Cholangiocarcinoma ◽

Biliary Epithelial Cell ◽

Microrna Profiling ◽

Cholangiocarcinoma Cell

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Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection

Hepatology ◽

10.1002/hep.26151 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1458-1468 ◽

Cited By ~ 206

Author(s):

Yun-Fan Sun ◽

Yang Xu ◽

Xin-Rong Yang ◽

Wei Guo ◽

Xin Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Cell Adhesion ◽

Epithelial Cell ◽

Tumor Cells ◽

Adhesion Molecule ◽

Poor Prognosis ◽

Curative Resection ◽

Cell Adhesion Molecule ◽

Epithelial Cell Adhesion Molecule

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Opposing Roles of FoxA1 and FoxA3 in Intrahepatic Cholangiocarcinoma Progression

International Journal of Molecular Sciences ◽

10.3390/ijms21051796 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1796

Author(s):

Raynoo Thanan ◽

Waleeporn Kaewlert ◽

Chadamas Sakonsinsiri ◽

Timpika Chaiprasert ◽

Napat Armartmuntree ◽

...

Keyword(s):

Stem Cell ◽

Transcription Factors ◽

Cell Differentiation ◽

Bile Duct ◽

Intrahepatic Cholangiocarcinoma ◽

Poor Prognosis ◽

Stem Cell Differentiation ◽

Biliary Epithelium ◽

Cancer Tissues ◽

Low Expression

Cholangiocarcinoma (CCA), a malignancy of biliary epithelium, is related to liver stem cell deregulation. FoxAs are a group of transcription factors that play critical roles in liver stem cell differentiation. In this study, the expression levels of FoxAs (i.e., FoxA1, FoxA2 and FoxA3) were detected in intrahepatic CCA tissues and the functions of FoxAs were studied in CCA cell lines. FoxA1 and FoxA2 were mainly localized in the nuclei of normal bile duct (NBD) cells and some of the cancer cells. Low expression of FoxA1 in CCA tissues (72%) was significantly correlated with poor prognosis. FoxA3 expression of CCA cells was localized in the nucleus and cytoplasm, whereas it was slightly detected in NBDs. High expression of FoxA3 in cancer tissues (61%) was significantly related to high metastasis status. These findings suggest the opposing roles of FoxA1 and FoxA3 in CCA. Moreover, the FoxA1-over-expressing CCA cell line exhibited a significant reduction in proliferative and invasive activities compared to control cells. Knockdown of FoxA3 in CCA cells resulted in a significant decrease in proliferative and invasive activities compared with control cells. Taken together, in CCA, FoxA1 is down-regulated and has tumor suppressive roles, whereas FoxA3 is up-regulated and has oncogenic roles.

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Vascular endothelial growth factor-C (VEGF-C) overexpression is correlated with poor prognosis in intrahepatic cholangiocarcinoma (CCC)

Gastroenterology ◽

10.1016/s0016-5085(01)81291-9 ◽

2001 ◽

Vol 120 (5) ◽

pp. A261-A261 ◽

Cited By ~ 1

Author(s):

Y PAIK ◽

Y KIM ◽

S PARK ◽

J CHUNG ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Intrahepatic Cholangiocarcinoma ◽

Poor Prognosis ◽

Vascular Endothelial ◽

Factor C ◽

Endothelial Growth Factor

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Induction of Stem Cell Like Cells from Mouse Embryonic Fibroblast by Short-Term Shear Stress and Vitamin C

Applied Sciences ◽

10.3390/app11041941 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1941

Author(s):

Seungmin Yeom ◽

Myung Chul Lee ◽

Shambhavi Pandey ◽

Jaewoon Lim ◽

Sangbae Park ◽

...

Keyword(s):

Stem Cells ◽

Shear Stress ◽

Stem Cell ◽

Vitamin C ◽

Suspension Culture ◽

Small Molecules ◽

Tumor Development ◽

Embryonic Stem ◽

Short Term ◽

External Stimuli

Induced pluripotent stem cells (iPSCs) are a good medicine source because of their potential to differentiate into various tissues or cells. However, traditionally, iPSCs made by specific transgenes and virus vectors are not appropriate for clinical use because of safety concerns and risk of tumor development. The goal of this research was to develop an alternative method for reprogramming, using small molecules and external stimuli. Two groups were established: short-term shear stress (STSS) under suspension culture and a combination of short-term shear stress and vitamin C (SSVC) under suspension culture. For STSS, the pipetting was carried out for cells twice per day for 2 min for 14 days in the embryonic stem cell (ES) medium. In the case of SSVC, the procedure was the same as for STSS however, its ES medium included 10 µM of vitamin C. After 14 days, all spheroids were picked and checked for pluripotency by ALP (alkaline phosphatase) assay and immunocytochemistry. Both groups partially showed the characteristics of stem cells but data demonstrated that the spheroids under shear stress and vitamin C had improved stem cell-like properties. This research showed the possibility of external stimuli and small molecules to reprogram the somatic cells without the use of transgenes.

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Clinical and prognostic significances of cancer stem cell markers in gastric cancer patients: a systematic review and meta-analysis

Cancer Cell International ◽

10.1186/s12935-021-01840-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Mahdieh Razmi ◽

Roya Ghods ◽

Somayeh Vafaei ◽

Maryam Sahlolbei ◽

Leili Saeednejad Zanjani ◽

...

Keyword(s):

Gastric Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Clinical Outcomes ◽

Cancer Progression ◽

Poor Prognosis ◽

Meta Analysis ◽

Disease Free Survival ◽

Stem Cell Markers ◽

Free Survival

Abstract Background Gastric cancer (GC) is considered one of the most lethal malignancies worldwide, which is accompanied by a poor prognosis. Although reports regarding the importance of cancer stem cell (CSC) markers in gastric cancer progression have rapidly developed over the last few decades, their clinicopathological and prognostic values in gastric cancer still remain inconclusive. Therefore, the current meta-analysis aimed to quantitatively re-evaluate the association of CSC markers expression, overall and individually, with GC patients’ clinical and survival outcomes. Methods Literature databases including PubMed, Scopus, ISI Web of Science, and Embase were searched to identify the eligible articles. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded or calculated to determine the relationships between CSC markers expression positivity and overall survival (OS), disease-free survival (DFS)/relapse-free survival (RFS), disease-specific survival (DSS)/ cancer-specific survival (CSS), and clinicopathological features. Results We initially retrieved 4,425 articles, of which a total of 66 articles with 89 studies were considered as eligible for this meta-analysis, comprising of 11,274 GC patients. Overall data analyses indicated that the overexpression of CSC markers is associated with TNM stage (OR = 2.19, 95% CI 1.84–2.61, P = 0.013), lymph node metastasis (OR = 1.76, 95% CI 1.54–2.02, P < 0.001), worse OS (HR = 1.65, 95% CI 1.54–1.77, P < 0.001), poor CSS/DSS (HR = 1.69, 95% CI 1.33–2.15, P < 0.001), and unfavorable DFS/RFS (HR = 2.35, 95% CI 1.90–2.89, P < 0.001) in GC patients. However, CSC markers expression was found to be slightly linked to tumor differentiation (OR = 1.25, 95% CI 1.01–1.55, P = 0.035). Sub-analysis demonstrated a significant positive relationship between most of the individual markers, specially Gli-1, Oct-4, CD44, CD44V6, and CD133, and clinical outcomes as well as the reduced survival, whereas overexpression of Lgr-5, Nanog, and sonic hedgehog (Shh) was not found to be related to the majority of clinical outcomes in GC patients. Conclusion The expression of CSC markers is mostly associated with worse outcomes in patients with GC, both overall and individual. The detection of a combined panel of CSC markers might be appropriate as a prognostic stratification marker to predict tumor aggressiveness and poor prognosis in patients with GC, which probably results in identifying novel potential targets for therapeutic approaches.

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