Prognostic value of multiple epithelial mesenchymal transition‑associated proteins in intrahepatic cholangiocarcinoma

Background/Aims: Intrahepatic cholangiocarcinoma (ICC) is a complicated condition, with difficult diagnosis and poor prognosis. The expression and clinical significance of the farnesoid X receptor (FXR), an endogenous receptor of bile acids, in ICC is not well understood. Methods: Western blotting and immunochemical analyses were used to determine the levels of FXR in 4 cholangiocarcinoma cell lines, a human intrahepatic biliary epithelial cell line (HIBEpic) and 322 ICC specimens, respectively, while quantitative reverse transcription polymerase chain reaction was used to detect the mRNA levels of FXR in cholangiocarcinoma cell lines. We evaluated the prognostic value of FXR expression and its association with clinical parameters. We determined the biological significance of FXR in ICC cell lines by agonist-mediated activation and lentivirus-mediated silence. IL-6 expression was tested by an enzyme-linked immunosorbent assay and flow cytometry. In vitro, cell proliferation was examined by Cell Counting Kit-8, migration and invasion were examined by wound healing and transwell assays; in vivo, tumor migration and invasion were explored in NOD-SCID mice. Results: FXR was downregulated in ICC cell lines and clinical ICC specimens. Loss of FXR was markedly correlated with aggressive tumor phenotypes and poor prognosis in patients with ICC. Moreover, FXR expression also had significant prognostic value in carbohydrate antigen 19-9 (CA19-9) negative patients. The expression of FXR was negatively correlated with IL-6 levels in clinical ICC tissues. FXR inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of ICC cells via suppression of IL-6 in vitro. Obeticholic acid, an agonist of FXR, inhibited IL-6 production, tumor growth and lung metastasis of ICC in vivo. Conclusions: FXR could be a promising ICC prognostic biomarker, especially in CA19-9 negative patients with ICC. FXR inhibits the tumor growth and metastasis of ICC via IL-6 suppression.

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Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma

OncoTargets and Therapy ◽

10.2147/ott.s36213 ◽

2012 ◽

pp. 255 ◽

Cited By ~ 22

Author(s):

Xing Yao ◽

Wang ◽

Zhou ◽

Wang ◽

Dai ◽

...

Keyword(s):

Protein Expression ◽

Intrahepatic Cholangiocarcinoma ◽

Epithelial Mesenchymal Transition ◽

Prognostic Significance ◽

Related Protein ◽

Mesenchymal Transition

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Epithelial–mesenchymal transition-associated miRNAs in ovarian carcinoma, with highlight on the miR-200 family: Prognostic value and prospective role in ovarian cancer therapeutics

Cancer Letters ◽

10.1016/j.canlet.2014.05.022 ◽

2014 ◽

Vol 351 (2) ◽

pp. 173-181 ◽

Cited By ~ 71

Author(s):

Maria Koutsaki ◽

Demetrios A. Spandidos ◽

Apostolos Zaravinos

Keyword(s):

Ovarian Cancer ◽

Ovarian Carcinoma ◽

Prognostic Value ◽

Epithelial Mesenchymal Transition ◽

Cancer Therapeutics ◽

Mesenchymal Transition

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Association of miR-141 and miR-200c with time to recurrence (TTR) and overall survival (OS) in resected non-small-cell lung cancer (NSCLC) adenocarcinoma (ADC) patients (p).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7547 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7547-7547

Author(s):

Marc Campayo ◽

Alfons Navarro ◽

Rut Tejero ◽

Maria L Cabanas ◽

Laureano Molins ◽

...

Keyword(s):

Surgical Resection ◽

Prognostic Value ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

Stage I ◽

Mesenchymal Transition ◽

Early Stage Nsclc ◽

Time To Recurrence ◽

Resected Nsclc

7547 Background: Surgical resection remains the standard curative treatment for early-stage NSCLC, but nearly 50% of p experience recurrence, highlighting the need for novel diagnostic and therapeutic strategies. Moreover, treatments in NSCLC are often histology-dependent, underlining the need for histology-related markers. MicroRNAs (miRNAs) are promising molecular markers in cancer, with marked differences in expression according to histology. miR-200 family members have been associated in vitro with the regulation of epithelial-mesenchymal transition. We have examined their impact on outcome in resected NSCLC p. Methods: We analyzed miRNA expression using TaqMan assays in 160 tumor samples from NSCLC p who had undergone surgical resection and correlated our findings with TTR and OS. Results: p characteristics: age, 67 (51-83); 140 male; 96 (60%) stage I, 34 (21.3%) stage II, 30 (18.7%) stage III; 77(48.1%) ADC, 71(44.4%) squamous cell carcinoma (SCC); 16 (9.1%) received adjuvant treatment. With a median follow-up of 28 months (m), 64 p (40%) had relapsed. TTR for the 107 p with high miR-200c was 26.7 m vs 100.2 m for the 52 p with low miR-200c (P=0.032). OS for p with high miR-200c was 71.2 m vs. 125 m for p with low miR-200c (P=0.01). TTR for 112 p with high miR-141 was 26.7 m vs. 100.2 m for 46 p with low miR-141 (P=0.06). OS for p with high miR-141 was 72 m vs. 118 m for p with low miR-141 (P=0.02). Interestingly, neither miR-200c nor miR-141 correlated with TTR or OS in SCC p. In contrast, in ADC p, the prognostic value of both miRNAs increased: miR-200c (TTR, P=0.01; OS, P<0.0001) and miR-141 (TTR, P=0.003; OS, P<0.0001). This prognostic value was maintained in the subgroup of stage I p: miR-200c (TTR, P=0.011; OS, P<0.001) and miR-141 (TTR, P=0.018; OS, P<0.001). In the multivariate analysis, miR-200c and miR-141 emerged as an independent prognostic factor for OS (OR: 3.2, P=0.006; OR:2.5, P=0.02, respectively) together with age>65 (OR: 3.3, P=0.001) and stage I (OR: 0.3, P=0.004). Conclusions: miR-200c and miR-141 expression is associated with TTR and OS in resected ADC but not in SCC NSCLC p.

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Comprehensive Multiple Molecular Profile of Epithelial Mesenchymal Transition in Intrahepatic Cholangiocarcinoma Patients

PLoS ONE ◽

10.1371/journal.pone.0096860 ◽

2014 ◽

Vol 9 (5) ◽

pp. e96860 ◽

Cited By ~ 12

Author(s):

Xiao-Yong Huang ◽

Chi Zhang ◽

Jia-Bin Cai ◽

Guo-Ming Shi ◽

Ai-Wu Ke ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Epithelial Mesenchymal Transition ◽

Molecular Profile ◽

Mesenchymal Transition

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Significance of the hedgehog pathway-associated proteins Gli-1 and Gli-2 and the epithelial-mesenchymal transition-associated proteins Twist and E-cadherin in hepatocellular carcinoma

Oncology Letters ◽

10.3892/ol.2016.4884 ◽

2016 ◽

Vol 12 (3) ◽

pp. 1753-1762 ◽

Cited By ~ 22

Author(s):

Hyung Wook Chun ◽

Ran Hong

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Hedgehog Pathway ◽

Mesenchymal Transition ◽

Associated Proteins ◽

Gli 1 ◽

E Cadherin

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The Prognostic Value of CD44 Expression in Epithelial–Mesenchymal Transition: Preliminary Data from Patients with Gastric and Esophageal Cancer

In Vivo ◽

10.21873/invivo.11017 ◽

2016 ◽

Vol 30 (6) ◽

pp. 939-944 ◽

Cited By ~ 1

Author(s):

DIMITRIOS SCHIZAS ◽

DEMETRIOS MORIS ◽

PRODROMOS KANAVIDIS ◽

ADAMANTIOS MICHALINOS ◽

ATHANASIOS SIOULAS ◽

...

Keyword(s):

Esophageal Cancer ◽

Preliminary Data ◽

Prognostic Value ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Cd44 Expression

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SQSTM1/p62 in Intrahepatic Cholangiocarcinoma Promotes Tumor Progression Via Epithelial-Mesenchymal Transition and Mitochondrial Function Maintenance

10.21203/rs.3.rs-964992/v1 ◽

2021 ◽

Author(s):

Jiafeng Chen ◽

Zheng Gao ◽

Xiaogang Li ◽

Yinghong Shi ◽

Zheng Tang ◽

...

Keyword(s):

Intrahepatic Cholangiocarcinoma ◽

Mitochondrial Function ◽

Epithelial Mesenchymal Transition ◽

Immunohistochemical Analysis ◽

Vital Role ◽

Loss Of Function ◽

Mesenchymal Transition ◽

Consumption Rates ◽

Invasive Capacity

Abstract Background: SQSTM1/p62, as a selective autophagy receptor, regulates multiple signaling pathways participating in the initiation and progression of tumors. Since metastasis is still a main cause for intrahepatic cholangiocarcinoma (ICC)-associated mortality, this study aimed to explore the mechanism of p62 promoting progression of ICC.Methods: Western blotting and immunohistochemical analysis were conducted to detect the expression level of protein p62 in ICC tissues. Subsequently, loss of function experiments was applied to define the role of p62 in the progression of ICC in vitro and in vivo. Mitochondrial function and mitophagy was evaluated by measuring oxygen consumption rates (OCR) and immunofluorescence detection respectively.Results: Here we identified expression of p62 was significantly upregulated in ICC specimens compared to normal tissue. And we further illustrated that p62 expression was positively correlated with lymph-node metastasis and poor prognosis. Loss of function assays revealed that p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lung metastasis in xenograft mouse model. Mechanistically, high expression of p62 induced epithelial-mesenchymal transition (EMT) with upregulation of Snail1, Vimentin and down-regulation of E-Cadherin. Moreover, OCR assays and immunofluorescence cell staining demonstrated that the autophagy-dependent function of p62 may play a vital role in maintaining mitochondrial function of ICC by mitophagy.Conclusions: These data provide new evidence and feasible mechanism that abundant p62 expression promote ICC progression, suggesting a promising therapeutic target for anti-metastatic strategies in ICC patients.

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