The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma

Sugiura, Katsura; Mishima, Takashi; Takano, Shigetsugu; Yoshitomi, Hideyuki; Furukawa, Katsunori; Takayashiki, Tsukasa; Kuboki, Satoshi; Takada, Mamoru; Miyazaki, Masaru; Ohtsuka, Masayuki

doi:10.1016/j.ajpath.2019.05.014

Cited by 37 publications

(31 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This inhibits YAP1 from entering the nucleus, where it would normally bind to the transcriptional enhancer factor (TEAD) and SMAD families of transcription factors, leading to the transcription of a number of oncogenic genes, including SOX9, amphiregulin, MYC and Gli1 (53)(54)(55). YAP1 overexpression is associated with tumorigenesis, epithelial-to-mesenchymal transition (EMT), in addition to tumor angiogenesis and invasion, physiological processes that have been previously demonstrated to lead to unfavorable prognoses in malignancies, including CCA, HCC, lung, brain, ovarian, breast, bladder and colon cancer (56)(57)(58)(59)(60). YAP1 expression was found to be an independent prognostic factor in both human and animal studies of CCA (57,59).…”

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

“…YAP1 overexpression is associated with tumorigenesis, epithelial-to-mesenchymal transition (EMT), in addition to tumor angiogenesis and invasion, physiological processes that have been previously demonstrated to lead to unfavorable prognoses in malignancies, including CCA, HCC, lung, brain, ovarian, breast, bladder and colon cancer (56)(57)(58)(59)(60). YAP1 expression was found to be an independent prognostic factor in both human and animal studies of CCA (57,59). Previous studies have demonstrated that liver-specific MOB1a/1b double knockout (61) and MST1/2 conditional knockout mice (62) exhibited phenotypically mixed HCC/CCA inducible tumors.…”

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

“…Until recently, targeting the Hippo/YAP1 signaling pathway has proved challenging due to its complexity and substantial crosstalk with other pathways. Verteporfin, a photodynamic drug that was traditionally used for treating macular degeneration, has recently emerged as a YAP/tafazzin (TAZ) inhibitor, where it has demonstrated promising preclinical results in cancers such as CCA (57). The combination of verteporfin and rapamycin was previously found to inhibit intrahepatic CCA cell proliferation and tumor growth (57), where verteporfin activated mTOR whilst inhibiting STAT3 phosphorylation in CCA (57).…”

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

See 2 more Smart Citations

Targeting cancer stem cells in cholangiocarcinoma (Review)

McGrath

et al. 2020

Int J Oncol

View full text Add to dashboard Cite

The incidence of cholangiocarcinoma has been increasing steadily over the past 50 years, but the survival rates remained low due to the disease being highly resistant to non-surgical treatment interventions. Cancer stem cell markers are expressed in cholangiocarcinoma, suggesting that they serve a significant role in the physiology of the disease. Cancer stem cells are frequently implicated in tumor relapse and acquired resistance to a number of therapeutic strategies, including chemotherapy, radiation and immune checkpoint inhibitors. Novel targeted therapies to eradicate cancer stem cells may assist in overcoming treatment resistance in cholangiocarcinoma and reduce the rates of relapse and recurrence. Several signaling pathways have been previously documented to regulate the development and survival of cancer stem cells, including Notch, janus kinase/STAT, Hippo/yes-associated protein 1 (YAP1), Wnt and Hedgehog signaling. Although pharmacological agents have been developed to target these pathways, only modest effects were reported in clinical trials. The Hippo/YAP1 signaling pathway has come to the forefront in the field of cancer stem cell research due to its reported involvement in epithelium-mesenchymal transition, cell adhesion, organogenesis and tumorigenesis. In the present article, recent findings in terms of cancer stem cell research in cholangiocarcinoma were reviewed, where the potential therapeutic targeting of cancer stem cells in this disease was discussed.

show abstract

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

Section: Signaling Pathways Involved In Csc Stemness and Potential Tamentioning

confidence: 99%

See 1 more Smart Citation

Targeting cancer stem cells in cholangiocarcinoma (Review)

McGrath

et al. 2020

Int J Oncol

View full text Add to dashboard Cite

show abstract

“…These results indicate that KLF5 might be involved in maintaining the CSC‐like properties in colon cancer cells. Furthermore, the effects of KLF5 on anoikis resistance in colon cancer cells were investigated because anoikis resistance is a major characteristic of CSCs that promotes metastasis 18 . In the anoikis assay, KLF5 knockdown resulted in a significant reduction in the number and size of colonies (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

High expression of Krüppel‐like factor 5 is associated with poor prognosis in patients with colorectal cancer

et al. 2020

Self Cite

View full text Add to dashboard Cite

Krüppel‐like factor 5 (KLF5) plays an oncogenic role and has diverse functions in cancer cells. However, correlation between KLF5 and clinical outcome has not been determined in patients with colorectal cancer and colorectal liver metastasis. Herein, we analyzed 65 patients with colorectal cancer who developed colorectal liver metastasis. Clinical effects were assessed through immunohistochemical analysis of primary colorectal cancer lesions and metastatic liver lesions. High expression of KLF5 in these tissues correlated with the presence of vascular invasion, elevated serum carbohydrate antigen 19‐9 levels, large diameters of metastatic liver tumors, and poor prognosis following surgery. Multivariate analyses revealed that high expression of KLF5 was an independent prognostic factor. Increased expression of KLF5 in both colorectal cancer primaries and colorectal liver metastasis was significantly associated with shorter overall survival time and time to surgical failure. Krüppel‐like factor 5 expression positively correlated with Ki‐67 and c‐Myc expression in colorectal cancer tissues. In vitro experiments with colon cancer cell lines showed that siRNA knockdown of KLF5 inhibited cell proliferation. Western blot analyses revealed that knockdown of KLF5 expression reduced cyclin D1 and c‐Myc expression. It also impaired the stem cell‐like properties of cancer cells in tumorsphere formation assays. Furthermore, anoikis assay indicated that KLF5 contributed to anoikis resistance. High KLF5 expression is associated with poor prognosis in patients with colorectal cancer and liver metastasis by promoting cell proliferation and cancer stem cell‐like properties.

show abstract

“…Benzoporphyrin derivative has been shown to disrupt the YAP/TAZ‐TEAD complex interaction without light activation , thereby blocking YAP‐driven oncogenic growth and overcoming resistance to cisplatin and paclitaxel . Additionally, previous studies have demonstrated that there is crosstalk between the YAP/TAZ signaling and the EGFR pathway , and EGFR can also contribute to drug resistance .…”

Section: Resultsmentioning

confidence: 99%

Harnessing the Potential Synergistic Interplay Between Photosensitizer Dark Toxicity and Chemotherapy

Baglo

Sorrin

Liang

et al. 2020

Photochem & Photobiology

View full text Add to dashboard Cite

The combination of photodynamic therapy and taxol‐ or platinum‐based chemotherapy (photochemotherapy) is an effective and promising cancer treatment. While the mechanisms of action of photochemotherapy are actively studied, relatively little is known about the cytotoxicity and molecular alterations induced by the combination of chemotherapy and photosensitizers without light activation in cancer cells. This study investigates the interplay between the photosensitizer benzoporphyrin derivative (BPD) without light activation and cisplatin or paclitaxel in two glioblastoma lines, U87 and U251. The combination effect of BPD and cisplatin in U87 cells is slightly synergistic (combination index, CI = 0.93), showing 1.8‐ to 2.6‐fold lower half‐maximal inhibitory concentrations (IC50) compared to those of individual drugs. In contrast, combining BPD and paclitaxel is slightly antagonistic (CI = 1.14) in U87 cells. In U251 cells, the combinations of BPD and cisplatin or paclitaxel are both antagonistic (CI = 1.24 and 1.34, respectively). Western blotting was performed to investigate changes in the expression levels of YAP, TAZ, Bcl‐2 and EGFR in U87 and U251 cells treated with BPD, cisplatin and paclitaxel, both as monotherapies and in combination. Our study provides insights into the molecular alterations in two glioma lines caused by each monotherapy and the combinations, in order to inform the design of effective treatments.

show abstract

The Expression of Yes-Associated Protein (YAP) Maintains Putative Cancer Stemness and Is Associated with Poor Prognosis in Intrahepatic Cholangiocarcinoma

Cited by 37 publications

References 40 publications

Targeting cancer stem cells in cholangiocarcinoma (Review)

Targeting cancer stem cells in cholangiocarcinoma (Review)

High expression of Krüppel‐like factor 5 is associated with poor prognosis in patients with colorectal cancer

Harnessing the Potential Synergistic Interplay Between Photosensitizer Dark Toxicity and Chemotherapy

Contact Info

Product

Resources

About