MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway

Du, Chunyang; Yi, Xiaomin; Li, Wenchao; Han, Tao; Liu, Zhaozhe; Ding, Zhenyu; Zheng, Zhendong; Piao, Ying; Yuan, Jianlin; Han, Yaling; Xie, Man‐Jiang; Xie, Xian-Jin

doi:10.1186/1471-2407-14-869

Cited by 36 publications

(41 citation statements)

References 51 publications

(49 reference statements)

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“…Studies have reported that MTDH is involved in the regulation of PTEN/AKT signalling pathway (31)(32)(33). Thus, western blotting analysis was utilized to detect PTEN, AKT and p-AKT protein expression levels in H522 and A549 cells after transfection with miR-584 mimics or miR-NC.…”

Section: Mir-584 Inhibits Activation Of Pten/akt Pathway In Nsclcmentioning

confidence: 99%

MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH

Zhang

Wang

2017

Exp Ther Med

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Abstract. Lung cancer is the third most frequent human malignant tumour and the leading cause of cancer-associated mortality worldwide. Emerging lines of evidence have demonstrated that microRNAs (miRNAs) are upregulated or downregulated in non-small cell lung cancer (NSCLC), and this phenomenon is involved in the regulation of various processes during tumorigenesis and progression, including tumour groWTh, apoptosis, cell invasion, and tumour metastasis. Therefore, understanding the molecular mechanism that associates abnormally expressed miRNAs with NSCLC formation and development may lead to the identification of novel diagnostic, and therapeutic targets for patients with NSCLC. miRNA-584 (miR-584) functions as a tumour suppressor in several types of cancer. However, the expression pattern, detailed biological function and underlying molecular mechanism of miR-584 in NSCLC remain unclear. Therefore, the present study detected the expression of miR-584 in NSCLC, investigated its role in NSCLC cells and determined its underlying molecular mechanism. In the current study, it was demonstrated that miR-584 was downregulated in NSCLC tissues and cell lines. Low miR-584 expression was correlated with tumour size, tumour node metastasis stage and distant metastasis. Overexpression of miR-584 inhibited cell proliferation and invasion in NSCLC. Additionally, metadherin was identified as a direct target gene of miR-584 in NSCLC as confirmed by a series of experiments. Moreover, upregulation of miR-584 was involved in the regulation of the phosphatase and tensin homolog/Akt serine/threonine kinase signalling pathway in NSCLC. Thus, miR-584 may serve as a tumor-suppressor, and the results of the present study provide a reference for future research into the potential mechanisms underlying NSCLC progression.

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Section: Mir-584 Inhibits Activation Of Pten/akt Pathway In Nsclcmentioning

confidence: 99%

MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH

Zhang

Wang

2017

Exp Ther Med

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“…Zhu et al (30) demonstrated that AEG1 regulates the expression of vascular endothelial growth factor via the PI3K/AKT signaling pathway, which may facilitate the metastasis of squamous cell carcinoma of the head and neck. AEG1 overexpression mediates trastuzumab resistance by phosphatase and tensin homolog inhibition through an NFκB-dependent pathway in HER2-positive breast cancer (29). The present study demonstrated that AEG1 is overexpressed in breast cancer cells, compared with normal mammary epithelial cells.…”

Section: Discussionmentioning

confidence: 52%

“…AEG1 has been reported to be associated with the activation of several signaling pathways including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor (NF)κB (27)(28)(29). Zhu et al (30) demonstrated that AEG1 regulates the expression of vascular endothelial growth factor via the PI3K/AKT signaling pathway, which may facilitate the metastasis of squamous cell carcinoma of the head and neck.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway

Dai

Wang

et al. 2017

Oncology Letters

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Abstract. Astrocyte elevated gene-1 (AEG1) was identified to be overexpressed in breast cancer, and to be associated with the development of breast cancer. In the present study, AEG1 was identified as highly expressed in the MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cell lines and was detected in the MCF-10A normal breast epithelial cell line. The present study established an AEG1-knockdown MCF-7 cell line to investigate the expression status of certain cancer-associated proteins. Western blotting demonstrated that AEG1 may affect cancer cell proliferation and invasion via activating the Wnt/β-catenin signaling pathway, a hypothesis that has been supported by cell function tests. The results of the present study demonstrated that when AEG1 was significantly overexpressed in breast cancer cells it promoted cell proliferation and invasion via activating the Wnt/β-catenin signaling pathway. Therefore, AEG1 may serve as a novel therapeutic target in breast cancer. IntroductionBreast cancer is a common type of malignancy; the incidence of the disease has increased in recent years worldwide, currently ranking first with respect to cancer-associated morbidity in women (1-3). The traditional methods of treatment include surgery, radiotherapy and chemotherapy for patients with advanced breast cancer exhibit poor efficacy (4). Therefore, the development of gene-targeted therapy for breast cancer requires further attention. Previous studies have revealed that numerous genes are involved in the occurrence and development of breast cancer, including cyclin D1, matrix metalloproteinases (MMPs) and E-cadherin (5-8). Astrocyte elevated gene-1 (AEG1) has also been investigated with respect to poor prognosis in breast cancer (9). AEG1 is a potentially crucial mediator of tumor malignancy and a key converging point of a complex network of oncogenic signaling pathways (10-12). Previous studies revealed that the AEG1 gene was significantly overexpressed in a number of types of malignant cells, and is associated with tumorigenesis, proliferation, invasion and metastasis (13,14). Statistics also demonstrated that AEG1 was upregulated in breast cancer tissue and positively correlated with clinical stage and lymph node metastasis (15).The Wnt signaling pathway is one of the most important intracellular signal transduction pathways, and it affects the activated state of multiple effector molecules downstream (16)(17)(18)(19). It is closely associated with a variety of human tumor developments, and serves an important role in breast cancer cell proliferation and invasion (20,21). However, the mechanisms that underlie the activation of the Wnt signaling pathway in various types of breast cancer have yet to be identified. β-catenin has been revealed as a central regulator in the Wnt signaling pathway, and is associated with disease progression and poor prognosis in breast cancer (22). Typically, during activation of the Wnt signaling pathway, β-catenin accumulates in the cytosol at high levels, binds to T-cell factor/lymphoid enhancer fac...

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“…A variety of cellular signalling pathways are regulated by MTDH, including PI3K/AKT nuclear factor-kappa B, Wnt/β-catenin, and MAPK/ERK [26]. Cheng et al found that MTDH mediated trastuzumab resistance through an NF-κB-dependent pathway and decreased PTEN expression [24]. Sujit et al noted that MTDH enhanced autophagy via a non-classical pathway.…”

Section: Introductionmentioning

confidence: 99%

“…MTDH has been reported to activate the expression of the multidrug resistance gene 1 (MDR1) protein [22]. Autophagy has also been shown to enhance drug resistance [23]; however, whether MTDH can mediate resistance to the anti-cancer drug fluorouracil (5-FU) through autophagy has not been investigated [24]. …”

Section: Introductionmentioning

confidence: 99%

Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ATG5 Pathway in Gastric Cancer

Pei

Luo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metadherin (MTDH) is overexpressed in some malignancies and enhances drug resistance; however, its role in gastric cancer (GC) and the underlying mechanisms remain largely unexplored. Here, we explore the mechanism by which MTDH induces drug resistance in GC. Methods: We analysed the level of MTDH in GC and adjacent normal gastric mucosal tissues by real-time quantitative PCR (q-PCR). We also analysed the level of autophagy by western blot analysis, confocal microscopy, and transmission electron microscopy after MTDH knockdown and overexpression, and examined fluorouracil (5-FU) resistance by Cell Counting Kit-8 at the same time. Finally, GC patient-derived xenograft tumours were used to demonstrate 5-FU resistance. An AMPK pathway inhibitor was applied to determine the molecular mechanisms of autophagy. Results: MTDH expression was significantly increased in the GC specimens compared with that in the adjacent normal gastric mucosal tissues. Further study showed a positive correlation between the expression level of MTDH and 5-FU resistance. MTDH overexpression in MKN45 cells increased the levels of P-glycoprotein (P-gp) and promoted 5-FU resistance, while inhibition of MTDH showed the opposite result. The simultaneous inhibition of autophagy and overexpression of MTDH decreased the levels of P-gp and inhibited 5-FU resistance. Moreover, MTDH induced AMPK phosphorylation, regulated ATG5 expression, and finally influenced autophagy, suggesting that MTDH may activate autophagy via the AMPK/ATG5 signalling pathway. Our findings reveal a unique mechanism by which MTDH promotes GC chemoresistance and show that MTDH is a potential target for improved chemotherapeutic sensitivity and GC patient survival. Conclusions: MTDH-stimulated cancer resistance to 5-FU may be mediated through autophagy activated by the AMPK/ATG5 pathway in GC.

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MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway

Cited by 36 publications

References 51 publications

MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH

MicroRNA-584 inhibits cell proliferation and invasion in non-small cell lung cancer by directly targeting MTDH

Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway

Autophagy Facilitates Metadherin-Induced Chemotherapy Resistance Through the AMPK/ATG5 Pathway in Gastric Cancer

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