STAT3 mediated upregulation of C-MET signaling acts as a compensatory survival mechanism upon EGFR family inhibition in chemoresistant breast cancer cells

Zhu, Yuying; Zhang, He; Han, Xingxing; Wang, Zhiyong; Cui, Yanfen; Tian, Ran; Wang, Zhaosong; Han, Baoai; Tian, Jianfei; Zhang, Fei; Niu, Ruifang

doi:10.1016/j.canlet.2021.07.048

Cited by 16 publications

(9 citation statements)

References 55 publications

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“…HGF, also called scatter factor, is a mesenchymal cell-derived cytokine that activates a tyrosine kinase signalling cascade via binding to the Met receptor. 56 The Met proto-oncogene plays a pivotal role in tumor invasion and metastasis, but the abnormal HGF/Met signaling in the human tumor microenvironment is not fully understood. 57 , 58 Pennacchietti et al.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition

Shi

Wang²,

Zhang³

et al. 2022

eBioMedicine

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Section: Discussionmentioning

confidence: 99%

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition

Shi

Wang²,

Zhang³

et al. 2022

eBioMedicine

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“…Quantitative reverse transcription PCR (qRT-PCR) analysis was performed with a AceQ qPCR SYBR Green Master Mix (Vazyme, China) as previously described [ 37 ]. In brief, cells treated with different doses of drugs (EPI, PTX and 5-FU) were lysed in Trizol, then total RNA were extracted according to the manufacturer’s instructions and reverse transcribed into cDNA by HiScript II Q RT SuperMix for qPCR (Vazyme, China).…”

Section: Methodsmentioning

confidence: 99%

Chemotherapy induces ACE2 expression in breast cancer via the ROS-AKT-HIF-1α signaling pathway: a potential prognostic marker for breast cancer patients receiving chemotherapy

et al. 2022

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Background Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system and a well-known functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The COVID-19 pandemic has brought ACE2 into the spotlight, and ACE2 expression in tumors and its relationship with SARS-COV-2 infection and prognosis of cancer patients have received extensive attention. However, the association between ACE2 expression and tumor therapy and prognosis, especially in breast cancer, remains ambiguous and requires further investigation. We have previously reported that ACE2 is elevated in drug-resistant breast cancer cells, but the exact function of ACE2 in drug resistance and progression of this malignant disease has not been explored. Methods The expression of ACE2 and HIF-1α in parental and drug-resistant breast cancer cells under normoxic and hypoxic conditions was analyzed by Western blot and qRT-PCR methods. The protein levels of ACE2 in plasma samples from breast cancer patients were examined by ELISA. The relationship between ACE2 expression and breast cancer treatment and prognosis was analyzed using clinical specimens and public databases. The reactive oxygen species (ROS) levels in breast cancer cells were measured by using a fluorescent probe. Small interfering RNAs (siRNAs) or lentivirus-mediated shRNA was used to silence ACE2 and HIF-1α expression in cellular models. The effect of ACE2 knockdown on drug resistance in breast cancer was determined by Cell Counting Kit 8 (CCK-8)-based assay, colony formation assay, apoptosis and EdU assay. Results ACE2 expression is relatively low in breast cancer cells, but increases rapidly and specifically after exposure to anticancer drugs, and remains high after resistance is acquired. Mechanistically, chemotherapeutic agents increase ACE2 expression in breast cancer cells by inducing intracellular ROS production, and increased ROS levels enhance AKT phosphorylation and subsequently increase HIF-1α expression, which in turn upregulates ACE2 expression. Although ACE2 levels in plasma and cancer tissues are lower in breast cancer patients compared with healthy controls, elevated ACE2 in patients after chemotherapy is a predictor of poor treatment response and an unfavorable prognostic factor for survival in breast cancer patients. Conclusion ACE2 is a gene in breast cancer cells that responds rapidly to chemotherapeutic agents through the ROS-AKT-HIF-1α axis. Elevated ACE2 modulates the sensitivity of breast cancer cells to anticancer drugs by optimizing the balance of intracellular ROS. Moreover, increased ACE2 is not only a predictor of poor response to chemotherapy, but is also associated with a worse prognosis in breast cancer patients. Thus, our findings provide novel insights into the spatiotemporal differences in the function of ACE2 in the initiation and progression of breast cancer.

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“…Yuying Zhu et al. ( 27 ) also found that up-regulated c-Met signal can be used as a compensation mechanism for weakening EGFR family signal so as to maintain the proliferation of chemotherapy resistant breast tumor cells. The combination of c-Met and EGFR targeted therapy was also found to synergistically inhibit proliferation of drug-resistant cells in vitro and in vivo .…”

Section: The Structure Of C-met/hgf and Its Tumor-related Signaling P...mentioning

confidence: 99%

“…Researches have demonstrated that c-Met normally mediates downstream signals by combining with its corresponding ligand, hepatocyte growth factor (HGF), to promote the proliferation and differentiation of tumor cells. It was also found that c-Met can also activate downstream pathways through signaling interaction with some carcinogenic molecules in the absence of ligands ( 26 , 27 ). Therefore, the mechanism of c-Met promoting tumor proliferation and drug resistance is complicated.…”

Section: Introductionmentioning

confidence: 99%

Opportunities and challenges of targeting c-Met in the treatment of digestive tumors

et al. 2022

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At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.

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STAT3 mediated upregulation of C-MET signaling acts as a compensatory survival mechanism upon EGFR family inhibition in chemoresistant breast cancer cells

Cited by 16 publications

References 55 publications

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition

Hypoxia activated HGF expression in pancreatic stellate cells confers resistance of pancreatic cancer cells to EGFR inhibition

Chemotherapy induces ACE2 expression in breast cancer via the ROS-AKT-HIF-1α signaling pathway: a potential prognostic marker for breast cancer patients receiving chemotherapy

Opportunities and challenges of targeting c-Met in the treatment of digestive tumors

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