The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer

Dong, Peixin; Konno, Yosuke; Watari, Hidemichi; Hosaka, Masayoshi; Noguchi, Masayuki; Sakuragi, Noriaki

doi:10.1186/s12967-014-0231-0

Cited by 111 publications

(85 citation statements)

References 116 publications

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“…initiation and progression through mechanisms such as cell growth and cell survival (Dong et al 2014b). Activation of PI3K may occur through growth factor receptors with tyrosine kinase activity (RTKs), G-protein coupled receptors, and oncogenes such as Ras, resulting in an accumulation of phosphatidylinositol-P3 at cell membranes, and subsequent activation of Akt, which in turn leads to upregulation of downstream targets including mTOR (Weigelt et al 2013).…”

Section: Cell Signaling Pathwaysmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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Section: Cell Signaling Pathwaysmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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“…In primary endometrial tumors, P1 had higher hypomethylation than benign endometrium [69] Micro-RNAs are small RNA molecules of non-coding RNA that play a central role in epigenetic control of gene transcription. Micro-RNA seems to have a differential profile on normal and tumoral endometrium and was correlated to PTEN-PI3K-AKT-mTOR pathway, which is involved in endometrial CSC and tumor progression [70]. A recent study evaluated the influence of microRNA-145 on OCT4 expression on human endometrial cell lines [58].…”

Section: Endometrial Cancer Stem Cellsmentioning

confidence: 99%

Clinical translation for endometrial cancer stem cells hypothesis

Carvalho

Laranjo

Abrantes

et al. 2015

Cancer Metastasis Rev

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Endometrial cancer is the most frequent gynecological malignancy in developed world. Cancer stem cells (CSC) are recognized as a small proportion of cells among the tumor cell population that are capable of self-renewal, aberrant differentiation, and escape homeostasis. This review aims to systematize the existing evidence of CSC of endometrial cancer and its clinical translation. In endometrial cancer, the cancer stem cell hypothesis has been studied in vitro using the isolation of colony forming units, side population with dye efflux capacity, and tumorospheres. The stem cell markers for endometrial cancer do not have uniform characteristics, albeit CD133 and aldehyde dehydrogenase (ALDH) were being associated with CSC phenotype. The application of endometrial CSC on xenograft models proves the tumorigenic capacity of this small group of cells. The metastatic process has been explained due to epithelial-mesenchymal transition (EMT) in which CSC seems to have a critical role. The chemoresistance is characteristic of CSC that in endometrial cancer has been shown in CSC phenotype and associated with CSC markers. The most ambitious potential for CSC is the development of targeted therapies. Its application on endometrial cancer is still poor, being a future perspective for research.

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“…Concomitantly, downregulation of the epithelial marker (E-cadherin) and upregulation of mesenchymal markers (vimentin, N-cadherin, fibronectin) and other related transcription factors (snail, slug, and twist) were also found in drug-resistant cancer cells with an EMT phenotype [12]. Additionally, the complex EMT process was reported to be related to the PI3K/Akt signaling pathway [21-24], which also participated in the cisplatin resistance of many cancer cells, including colorectal cancer [25], lung cancer [26], and ovarian cancer [27]. However, whether the EMT process is correlated with cisplatin resistance in NSCLC is still unclear.…”

Section: Introductionmentioning

confidence: 99%

CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway

Zhang

Sun

et al. 2017

Cell Physiol Biochem

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Background/Aims: Chemoresistance has been a major obstacle to the effective treatment of lung cancer. Previously, we found that contactin-1 (CNTN-1) is related to cisplatin resistance in lung adenocarcinoma. Here, we aimed to investigate the underlying mechanism behind the role of CNTN-1 in cisplatin resistance in lung adenocarcinoma. Methods: EMT-associated phenotypes, including alterations in cellular morphology and marker (E-cadherin, N-cadherin and Vimentin) expression, were compared between A549 cells and A549/DDP cells (a cisplatin-resistant cell line of lung adenocarcinoma with abnormal CNTN-1 expression) by using real-time time PCR and Western blotting. Other methods, including CNTN-1 overexpression in A549 cells and CNTN-1 knockdown in A549/DDP cells, were also used to investigate the role of CNTN-1 in mediating the EMT phenotype and thr resulting cisplatin resistance and malignant progression of cancer cells in vitro and in vivo. Results: A549/DDP cells exhibited an EMT phenotype and aggravated malignant behaviors. CNTN-1 knockdown in A549/DDP cells partly reversed the EMT phenotype, increased drug sensitivity, and attenuated the malignant progression whereas CNTN-1 overexpression in A549 cells resulted in the opposite trend. Furthermore, the PI3K/Akt pathway was involved in the effects of CNTN-1 on EMT progression in A549/DDP cells, verified by the xenograft mouse model. Conclusion: CNTN-1 promotes cisplatin resistance in human cisplatin-resistant lung adenocarcinoma through inducing the EMT process by activating the PI3K/Akt signaling pathway. CNTN-1 may be a potential therapeutic target to reverse chemoresistance in cisplatin-resistant lung adenocarcinoma.

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The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer

Cited by 111 publications

References 116 publications

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Clinical translation for endometrial cancer stem cells hypothesis

CNTN-1 Enhances Chemoresistance in Human Lung Adenocarcinoma Through Induction of Epithelial-Mesenchymal Transition by Targeting the PI3K/Akt Pathway

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