Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma

Seol, Min-A; Chu, In-Sun; Lee, Mi-Jin; Yu, Goung-Ran; Cui, Xiang-Dan; Cho, Baik-Hwan; Ahn, Eun‐Kyung; Leem, Sun‐Hee; Kim, In-Hee; Kim, Dae‐Ghon

doi:10.1186/1471-2407-11-78

Cited by 45 publications

(43 citation statements)

References 53 publications

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“…Moreover, TWIST nuclear expression was significantly correlated with high N-cadherin expression [41]. More particularly, TWIST1 was highly expressed in poorly differentiated and sarcomatous CCA tissues suggesting a close relationship between EMT-TFs and the appearance of a mesenchymal phenotype [58].…”

mentioning

confidence: 85%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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mentioning

confidence: 85%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

124

122

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“…Firstly, in CC, KIAA1114 expression was significantly higher in sarcomatoid SCK cells than adenocarcinomatous cell lines, JCK, Cho-CK, and Choi-CK (Figure 2A). A prior study showed that SCK cells not only possessed strong resistance to chemotherapeutic agents, but also expressed elevated levels of genes involved in cancer progression and metastasis as well as EMT-associated markers [23, 24]. As sarcomatoid CCs are known to be more aggressive and have worse prognosis than adenocarcinomatous CCs [24], increased expression of KIAA1114 may contribute to the acquisition of an aggressive phenotype in CC.…”

Section: Resultsmentioning

confidence: 99%

KIAA1114, a full-length protein encoded by the trophinin gene, is a novel surface marker for isolating tumor-initiating cells of multiple hepatocellular carcinoma subtypes

et al. 2014

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Identification of novel biomarkers for tumor-initiating cells (TICs) is of critical importance for developing diagnostic and therapeutic strategies against cancers. Here we identified the role of KIAA1114, a full-length translational product of the trophinin gene, as a distinctive marker for TICs in human liver cancer by developing a DNA vaccine-induced monoclonal antibody targeting the putative extracellular domain of KIAA1114. Compared with other established markers of liver TICs, KIAA1114 was unique in that its expression was detected in both alpha fetoprotein (AFP)-positive and AFP-negative hepatocellular carcinoma (HCC) cell lines with the expression levels of KIAA1114 being positively correlated to their tumorigenic potentials. Notably, KIAA1114 expression was strongly detected in primary hepatic tumor, but neither in the adjacent non-tumorous tissue from the same patient nor normal liver tissue. KIAA1114high cells isolated from HCC cell lines displayed TIC-like features with superior functional and phenotypic traits compared to their KIAA1114low counterparts, including tumorigenic abilities in xenotransplantation model, in vitro colony- and spheroid-forming capabilities, expression of stemness-associated genes, and migratory capacity. Our findings not only address the value of a novel antigen, KIAA1114, as a potential diagnostic factor of human liver cancer, but also as an independent biomarker for identifying TIC populations that could be broadly applied to the heterogeneous HCC subtypes.

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“…Seol et al [7] reported that CC cell lines did not express SPARC and its expression was barely detected in CC patient tissues. In the present study, we confirmed that BTC cell lines express at least much less Sparc than nonmalignant cholangiocytes (MMNK-1).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, high SPARC levels inversely correlate with good prognosis of gastric [10], pancreatic [11] and prostate cancer [12] but are a favorable marker for colorectal [13] and ovarian cancer [14]. Seol et al [7] have reported that CC cells expressed lower SPARC than normal biliary cells. However, the role of this decreased expression in BTC and of its possible correlation with clinical features is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells

et al. 2019

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Background: Biliary tract cancers (BTCs) have a poor prognosis. BTCs are characterized by a prominent desmoplastic reaction which possibly contributes to the aggressive phenotype of this tumor. The desmoplastic reaction includes excessive production and deposition of extracellular matrix proteins such as periostin, secreted protein acidic and rich in cysteine (SPARC), thrombospondin-1, as well as accumulation of α-smooth muscle actin-positive cancer-associated fibroblasts and immune cells, secreting growth factors and cytokines including transforming growth factor (TGF)-β. In the present study, we investigated the expression of SPARC in BTC as well as its possible regulation by TGF-β. Methods: Expression levels of Sparc, TGF-β1 and its receptor ALK5 were evaluated by quantitative real-time PCR in 6 biliary tract cell lines as well as 1 immortalized cholangiocyte cell line (MMNK-1). RNAs from tumor samples of 7 biliary tract cancer patients were analyzed for expression of Sparc, TGF-β type II receptor (TbRII) as well as Twist and ZO-1. MMNK-1 cells were stimulated with TGF-β for 24 h, and Sparc, ZO-1 and E-Cadherin expressions were determined. The presence of SPARC protein was analyzed by immunohistochemistry in tumor specimens from 10 patients. Results: When comparing basal Sparc transcript levels in diverse BTC cell lines to MMNK-1 cells, we found that it was strongly downregulated in all cancer cell lines. The remaining expression levels were higher in highly differentiated cell lines (CCSW1, MZChA1, MZChA2 and TFK-1) than in less differentiated and undifferentiated ones (BDC, SKChA1). Expression of Sparc in BTC patient samples showed a significant positive correlation with expression of the epithelial marker ZO-1. In contrast, the mesenchymal marker Twist and the TbRII showed a trend of negative correlation with expression of Sparc in these samples. TGF-β exposure significantly downregulated Sparc expression in MMNK-1 cholangiocytes in vitro in parallel to downregulation of epithelial markers (E-Cadherin and ZO-1). Finally, SPARC immunostaining was performed in 10 patient samples, and the correlation between absence of SPARC and survival times was analyzed. Conclusions: These data imply that a decrease in SPARC expression is correlated with dedifferentiation of BTC cells resulting in enhanced EMT being possibly mediated by TGF-β. Thereby SPARC levels might be a marker for individual prognosis of a patient, and strategies aiming at inhibition of SPARC downregulation might have potential for new future therapies.

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Genome-wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma

Cited by 45 publications

References 53 publications

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

KIAA1114, a full-length protein encoded by the trophinin gene, is a novel surface marker for isolating tumor-initiating cells of multiple hepatocellular carcinoma subtypes

Downregulation of SPARC Is Associated with Epithelial-Mesenchymal Transition and Low Differentiation State of Biliary Tract Cancer Cells

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