scholarly journals TIMP-2 Regulates 5-Fu Resistance via the ERK/MAPK Signaling Pathway in Colorectal Cancer

2020 ◽  
Author(s):  
Guolin Zhang ◽  
Xin Luo ◽  
Jianbin Xu ◽  
Wei Zhang ◽  
Engeng Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Signaling Pathway ◽  
Resistance Mechanism ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Erk Mapk ◽  
Colorectal Cancer Patients ◽  
Autocrine Mechanism

Abstract Background: 5-Fluorouracil (5-Fu) is the first-line chemotherapeutic drug in the treatment of colorectal cancer. The efficiency of 5-Fu is limited by drug resistance in colorectal cancer patients. This study was aimed to define the functions of tissue inhibitor metalloproteinases 2 (TIMP-2) in the 5-Fu resistance to colorectal cancer and investigate its potential mechanism.Methods: Cytokine array, ELISA and RT-qPCR were performed to detect cytokine expression levels. Western blot and immunohistochemistry were used to show the differential expression of proteins. In addition, cell viability was detected by CCK-8.Results: We established that there is an up-regulation in the expression of the TIMP-2 in colorectal cancer patients. This up-regulation in TIMP-2 expression was evident in 5-Fu resistant colorectal cancer patients and resulted in a poor prognosis. Besides, in vivo, clinical studies and patient-derived xenograft (PDX) models confirmed that TIMP-2 was highly expressed in the 5-Fu-resistant colorectal cancer. We deduced an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway via an autocrine mechanism. The 5-Fu resistance could overcome by the inhibition of TIMP-2 by anti-TIMP-2 antibody or ERK/MAPK by U0126.Conclusion: Our findings identify a TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism in colorectal cancer. Moreover, we recommend the use of an ERK/MAPK signal pathway inhibitor or TIMP-2-mediated immunotherapy for 5-Fu resistant colorectal cancer.

scholarly journals TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer

Aging ◽  
2022 ◽  
Author(s):  
Guolin Zhang ◽  
Xin Luo ◽  
Zian Wang ◽  
Jianbin Xu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Erk Mapk

scholarly journals Aldolase A Promotes Proliferation and Metastasis of Colorectal Cancer through Targeting COPS6 and Regulating MAPK Signaling Pathway

2021 ◽  
Author(s):  
Ya Lu ◽  
Yuan Zhang ◽  
Hui Zhang ◽  
Yue Zhu ◽  
Junying Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Invasion And Migration ◽  
Proliferation And Metastasis ◽  
And Migration ◽  
Aldolase A

Abstract Background: Colorectal cancer (CRC) is a serious threat to human health, and its underlying mechanisms needs further explored. Aldolase A (ALDOA) has received increasing attention for its reported association with multiple cancers, but the function and mechanism of ALDOA in CRC remain unclear. We aimed to evaluate the biological role of ALDOA in CRC.Methods: The stable ALDOA knockdown or overexpression cell lines were established for subsequent experiments. The qRT-PCR and western blotting were used to detect the expression of ALDOA and COPS6 and the relative protein levels of epithelial-mesenchymal transition (EMT) and MAPK signaling pathway. Immunofluorescence (IF) assay was applied to determine ALDOA localization. CCK-8, transwell, and wound healing assays were performed to evaluate CRC cell proliferation, invasion, and migration. Mouse xenograft models were established to verify the effect of ALDOA on CRC cell growth in vivo. Immunoprecipitation (IP) assay and mass spectrometry (MS) analysis were conducted to identify the interactions between ALDOA and COPS6.Results: ALDOA was overexpressed in CRC tissues and cell lines. Silencing ALDOA significantly impaired the proliferation, invasion and migration of CRC cells in vitro, and obviously decreased the growth of CRC cells in vivo. Mechanically, ALDOA bound to and regulated COPS6, and the promoting effects of upregulated ALDOA on CRC cell proliferation and metastasis were inhibited by the depletion of COPS6. Besides, EMT program and MAPK signaling pathway were activated by ALDOA overexpression.Conclusion: ALDOA facilitated the proliferation, invasion and migration of CRC through binding and regulating COPS6, inducing EMT and activating MAPK signaling pathway.

scholarly journals USP11 promotes growth and metastasis of colorectal cancer via PPP1CA-mediated activation of ERK/MAPK signaling pathway

EBioMedicine ◽  
2019 ◽  
Vol 48 ◽  
pp. 236-247 ◽  
Author(s):  
Hongze Sun ◽  
Baochi Ou ◽  
Senlin Zhao ◽  
Xueni Liu ◽  
Liwei Song ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Erk Mapk

scholarly journals Elevated microRNA-145 inhibits the development of oral squamous cell carcinoma through inactivating ERK/MAPK signaling pathway by down-regulating HOXA1

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Junhai Ding ◽  
Dubin Sun ◽  
Pengfeng Xie
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Viability ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Erk Mapk

AbstractBackground: Oral cancer is one of the most frequent solid cancers worldwide, and oral squamous cell carcinoma (OSCC) constitutes approximately 90% of oral cancers. The discovery of reliable prognostic indicators would be a potential strategy for OSCC treatment. In the present study, we aim to explore the underlying mechanism by which microRNA-145 (miR-145) affected OSCC. Methods: Forty-eight patients diagnosed with OSCC were enrolled to obtain the OSCC tissues and adjacent normal tissues. The targeting relationship between miR-145 and Homeobox A1 (HOXA1) was verified. In order to assess the effects of miR-145 in OSCC and the detailed regulatory mechanism, the SCC-9 cell line was adopted, in which expression of miR-145 and HOXA1 were altered by transfection. Then, a series of in vitro and in vivo experiments were performed to evaluate the cell viability, migration, invasion, and tumor growth. Results: miR-145 was poorly expressed and HOXA1 was highly expressed in OSCC. HOXA1 was verified as a target of miR-145 to mediate the activation of the extracellular signal-regulated kinase/mitogen activated protein kinase (ERK/MAPK) signaling pathway. In the circumstance of miR-145 elevation or HOXA1 depletion, the SCC-9 cell line manifested with inhibited cell viability, invasion, and migration in vitro, coupled with reduced tumor growth in vivo, with a decreased expression of ERK/MAPK signaling pathway-related genes/proteins. Conclusion: These findings suggested that miR-145 can inhibit HOXA1 to inactivate the ERK/MAPK signaling pathway, thereby suppressing OSCC cell proliferation, migration, and invasion to further inhibit the development of OSCC, highlighting a novel therapeutic target for the OSCC treatment.

scholarly journals Cholesterol Enhances Colorectal Cancer Progression via ROS Elevation and MAPK Signaling Pathway Activation

2017 ◽  
Vol 42 (2) ◽  
pp. 729-742 ◽  
Author(s):  
Caihua Wang ◽  
Peiwei Li ◽  
Junmei Xuan ◽  
Chunpeng Zhu ◽  
Jingjing Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
High Fat Diet ◽  
Ldl Receptor ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
High Fat

Background/Aims: Elevated serum cholesterol levels were linked to a higher risk of colorectal adenoma and colorectal cancer (CRC), while the effect of cholesterol on CRC metastasis has not been widely studied. Methods: CRC patients were enrolled to evaluate the association between low-density lipoprotein cholesterol (LDL) and CRC metastases, and LDL receptor (LDLR) level of the CRC tissue was assessed by immunohistochemistry. The effects of LDL on cell proliferation, migration and stemness were assessed in CRC cells in vitro, and the effects of high fat diet (HFD) on tumor growth and intestinal tumorigenicity were investigated in vivo. ROS assays, gene expression array analysis and western blot were used to explore the mechanisms of LDL in CRC progression. Results: The level of LDL was positively correlated with liver metastases, and a higher level of LDL receptor (LDLR) expression was associated with advanced N and M stages of CRC. In vitro, LDL promoted the migration and sphere formation of CRC cells and induced upregulated expression of “stemness” genes including Sox2, Oct4, Nanog and Bmi 1. High-fat diet (HFD) significantly enhanced tumor growth in vivo, and was associated with a shorter intestinal length in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Furthermore, LDL significantly elevated reactive oxygen species (ROS) levels and Whole Human Genome Microarray found 87 differentially expressed genes between LDL-treated CRC cells and controls, which were largely clustered in the MAP kinase (MAPK) signaling pathway. Conclusions: LDL enhances intestinal inflammation and CRC progression via activation of ROS and signaling pathways including the MAPK pathway. Inflammation is strongly associated with cancer initiation, and the role of LDL in intestinal tumorigenicity should be further explored.

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