PBX3 promotes migration and invasion of colorectal cancer cellsviaactivation of MAPK/ERK signaling pathway

Abstract Background MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism. Methods To investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays. Results We find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3′-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3−/− mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo. Conclusion Our study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

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RNA-Binding Protein IMP3 is a Novel Regulator of MEK1/ERK Signaling Pathway in the Progression of Colorectal Cancer through the Stabilization of MEKK1 mRNA

10.21203/rs.3.rs-152463/v1 ◽

2021 ◽

Author(s):

Meng Zhang ◽

Senlin Zhao ◽

Cong Tan ◽

Yanzi Gu ◽

Xuefeng He ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Erk Signaling ◽

Luciferase Reporter ◽

Migration And Invasion

Abstract Background MEK1/ERK signaling pathway plays an important role in most tumor progression, including colorectal cancer (CRC), however, MEK1-targeting therapy has little effective in treating CRC patients, indicating there may be a complex mechanism to activate MEK1/ERK signaling pathway except RAS activated mechanism. Methods To investigate the clinical significance of IMP3, we analyzed its expression levels in publicly available dataset and samples from Fudan University Shanghai Cancer Center. The effects of IMP3 on proliferation, migration, and invasion were determined by in vitro and in vivo experiments. To investigate the role of IMP3 in colon carcinogenesis, conditional IMP3 knockout C57BL/6 mice was generated. The IMP3/MEKK1/MEK/ERK signaling axis in CRC was screened and validated by RNA-sequencing, RNA immunoprecipitation, luciferase reporter and western blot assays. Results We find RNA binding protein IMP3 directly bind to MEKK1 mRNA 3’-UTR, which regulates its stability, promote MEKK1 expression and sequentially activates MEK1/ERK signaling. Functionally, IMP3 promote the malignant biological process of CRC cells via MEKK1/MEK1/ERK signaling pathway both in vitro and in vivo, Moreover, IMP3−/− mice show decreased the expression of MEKK1 as well as colorectal tumors compared with wild-type mice after treatment with azoxymethane/dextran sodium sulfate. Clinically, the expression of IMP3 and MEKK1 are positive correlated, and concomitant IMP3 and MEKK1 protein levels negatively correlate with metastasis in CRC patients. In addition, MEK1 inhibitor in combination with shRNA-IMP3 have a synergistic effect both in vitro and in vivo. Conclusion Our study demonstrates that IMP3 regulates MEKK1 in CRC, thus activating the MEK1/ERK signaling in the progression of colorectal cancer, Furthermore, these results provide new insights into potential applications for combining MEK1 inhibitors with other target therapy such as IMP3 in preclinical trials for CRC patients.

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Overexpression of microRNA-29b inhibits epithelial-mesenchymal transition and angiogenesis of colorectal cancer through the ETV4/ERK/EGFR axis

Cancer Cell International ◽

10.1186/s12935-020-01700-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yin Leng ◽

Zhixian Chen ◽

Hui Ding ◽

Xiaoxu Zhao ◽

Li Qin ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Cancer Progression ◽

Epithelial Mesenchymal Transition ◽

Vasculogenic Mimicry ◽

Erk Signaling ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Luciferase Reporter Gene ◽

Mesenchymal Transition

Abstract Background Recent studies have reported the involvement of microRNA-29 (miR-29) family members in human cancers through their ability to regulate cellular functions. The present study investigated biological function of miR-29b in colorectal cancer (CRC). Methods CRC tissues and adjacent normal tissues were collected and the expression of ETV4 and miR-29b in the tissues were identified. The relationship between ETV4 and miR-29b or ETV4 expression and the EGFR promoter was identified using dual-luciferase reporter gene and CHIP assays. The proliferation, invasion, migration, and apoptosis of CRC HCT116 cells were assayed using MTT assay, Scratch test, Transwell assay, and flow cytometry, respectively. Also, expression of epithelial-mesenchymal transition (EMT) markers, angiogenic factors, and vasculogenic mimicry formation were evaluated using RT-qPCR and Western blot. Results ETV4 was upregulated, while miR-29b expression was decreased in CRC tissues. ETV4 was identified as a target gene of miR-29b, which in turn inactivated the ERK signaling pathway by targeting ETV4 and inhibiting EGFR transcription. Transfection with miR-29b mimic, siRNA-ETV4, or ERK signaling pathway inhibitor U0126 increased expression of E-cadherin and TSP-1, and CRC cell apoptosis, yet reduced expression of ERK1/2, MMP-2, MMP-9, Vimentin, and VEGF, as well as inhibiting EMT, angiogenesis, and CRC cell migration and invasion. The EMT, angiogenesis and cancer progression induced by miR-29b inhibitor were reversed by siRNA-mediated ETV4 silencing. Conclusions miR-29b suppresses angiogenesis and EMT in CRC via the ETV4/ERK/EGFR axis.

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CIP4 Targeted to Recruit GTP-Cdc42 Involving in Invadopodia Formation Through NF-κB Signaling Pathway Promotes Invasion and Metastasis of Colorectal Cancer

10.21203/rs.3.rs-433625/v1 ◽

2021 ◽

Author(s):

Zhiyan Hu ◽

Jiaxian Zhu ◽

Yidan Ma ◽

Ting Long ◽

Lingfang Gao ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Tumor Metastasis ◽

Migration And Invasion ◽

Downstream Signaling ◽

And Function ◽

Downstream Signaling Pathway ◽

Invadopodia Formation

Abstract Background CIP4 (Cdc42-interacting protein 4), a member of the F-BAR family which plays an important role in regulating cell membrane and actin, has been reported to interact with Cdc42 and closely associated with tumor invadopodia formation. However, the specific mechanism of the interaction between CIP4 and Cdc42 as well as the downstream signaling pathway in response in colorectal cancer (CRC) remains unknown, which is worth exploring for its impact on tumor infiltration and metastasis. Methods Immunohistochemistry and western blot analyses were performed to detect the expression of CIP4 and Cdc42. Their relationship with CRC clinicopathological characteristics was further analyzed. Wound-healing, transwell migration and invasion assays tested the effect of CIP4 on cells migration and invasion ability in vitro, and the orthotopic xenograft colorectal cancer mouse mode evaluated the tumor metastasis in vivo. The invadopodia formation and function were assessed by immunofluorescence, scanning electron microscopy (SEM) and matrix degradation assay. The interaction between CIP4 and Cdc42 was confirmed by co-immunoprecipitation (co-IP) and GST-Pull down assays. Immunofluorescence was used to observed the colocalization of CIP4, GTP-Cdc42 and invadopodia. The related downstream signaling pathway was investigated by western blot and immunofluorescence. Results CIP4 expression was significantly higher in human colorectal cancer tissues and correlated with the CRC infiltrating depth and metastasis as well as the lower survival rate in patients. In cultured CRC cells, knockdown of CIP4 inhibited cell migration and invasion ability in vitro and the tumor metastasis in vivo, while overexpression of CIP4 confirmed the opposite situation by promoting invadopodia formation and matrix degradation ability. In addition, we identified GTP-Cdc42 as a directly interactive protein of CIP4, which was upregulated and recruited by CIP4 to participate in this process. Furthermore, activated NF-κB signaling pathway was found in CIP4 overexpression CRC cells contributing to invadopodia formation while inhibition of either CIP4 or Cdc42 led to suppression of NF-κB pathway resulted in decrease quantity of invadopodia. Conclusion Our findings suggested that CIP4 targets to recruit GTP-Cdc42 and directly combines with it to accelerate invadopodia formation and function by activating NF-κB signaling pathway, thus promoting CRC infiltration and metastasis.

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Celastrus Orbiculatus Extract Suppresses Migration and Invasion of Gastric Cancer by Inhibiting Prohibitin and c-Raf/ERK Signaling Pathway

International Journal of Pharmacology ◽

10.3923/ijp.2019.40.49 ◽

2018 ◽

Vol 15 (1) ◽

pp. 40-49 ◽

Cited By ~ 1

Author(s):

Guang Zhu ◽

Hai-bo Wang ◽

Feng Jin ◽

Li-de Tao ◽

Dan Li ◽

...

Keyword(s):

Gastric Cancer ◽

Signaling Pathway ◽

Erk Signaling ◽

Migration And Invasion ◽

Celastrus Orbiculatus

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CLDN8 promotes colorectal cancer cell proliferation, migration, and invasion by activating MAPK/ERK signaling

Cancer Management and Research ◽

10.2147/cmar.s189558 ◽

2019 ◽

Vol Volume 11 ◽

pp. 3741-3751 ◽

Cited By ~ 6

Author(s):

Bo Cheng ◽

Aimei Rong ◽

Quanbo Zhou ◽

Wenlu Li

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Erk Signaling ◽

Colorectal Cancer Cell ◽

Migration And Invasion ◽

Cancer Cell Proliferation

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MicroRNA‐23a inhibits melanoma cell proliferation, migration, and invasion in mice through a negative feedback regulation of sdcbp and the MAPK/ERK signaling pathway

IUBMB Life ◽

10.1002/iub.1979 ◽

2018 ◽

Vol 71 (5) ◽

pp. 587-600 ◽

Cited By ~ 2

Author(s):

Shelian Lu ◽

Qunyuan Xu

Keyword(s):

Cell Proliferation ◽

Signaling Pathway ◽

Melanoma Cell ◽

Negative Feedback ◽

Feedback Regulation ◽

Erk Signaling ◽

Migration And Invasion ◽

Negative Feedback Regulation ◽

Melanoma Cell Proliferation

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The Long Non-Coding RNA CRNDE Promotes Colorectal Carcinoma Progression by Competitively Binding miR-217 with TCF7L2 and Enhancing the Wnt/β-Catenin Signaling Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000475941 ◽

2017 ◽

Vol 41 (6) ◽

pp. 2489-2502 ◽

Cited By ~ 47

Author(s):

Bo Yu ◽

Xuan Ye ◽

Qiong Du ◽

Bin Zhu ◽

Qing Zhai

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Western Blotting ◽

Migration And Invasion ◽

Down Regulation ◽

Over Expression ◽

Non Coding Rna ◽

Colorectal Cancer Cells ◽

Long Non Coding Rna

Background/Aims: The long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) contributes to the proliferation and migration of tumors. However, its molecular mechanism underlying gastric cancer remains unknown. In the present study, we investigated whether CRNDE was involved in the development of colorectal cancer via the binding of microRNA (miR)-217 with transcription factor 7-like 2 (TCF7L2) to enhance the Wnt signaling pathway. Methods: Quantitative polymerase chain reaction was used to detect CRNDE, miR-217 and TCF7L2 in colorectal cancer tissues and cells. The CCK-8 assay, wound healing assay, and Transwell assay were used to detect cell proliferation, migration and invasion, respectively. Western blotting and luciferase activity assays were used to identify CRNDE and TCF7L2 as one of the direct targets of miR-217. The activity of the Wnt/β-catenin signaling pathway was analyzed by the TOPflash assay, and the subcellular localization of β-catenin and TCF7L2 was analyzed by western blotting and confocal microscopy. Results: In this study, we found that high expression of CRNDE is negatively correlated with low expression of miR-217 in colorectal cancer tissue and colorectal cancer cells. The dual luciferase reporter analysis showed that miR-217 is bound to CRNDE and TCF7L2 and negatively regulate their expression. CRNDE down-regulation inhibited the cell proliferation, migration and invasion in vitro and in vivo and the inhibitions were both completely blocked after miR-217 inhibition or TCF7L2 overexpression. Finally, TOPflash analysis showed that the activity of Wnt/β-catenin signaling is inhibited by CRNDE down-regulation and rescued by TCF7L2 over-expression. Consistently immunostaining and western blotting analysis showed that the expression of b-catenin and TCF7L2 in the nucleus was significantly decreased by CRNDE down-regulation and was rescued by TCF7L2 over-expression. Conclusions: The present study suggest that CRNDE involves in the cell proliferation, migration and invasion of colorectal cancer cells via increasing the expression of TCF7L2 and activity of Wnt/β-catenin signaling through binding miR-217 competitively.

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