PIPKI<i>γ</i> Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling

Xue, Junli; Ge, Xiaoxiao; Zhao, Wei; Xue, Lu; Dai, Congqi; Lin, Feng; Peng, Wei

doi:10.1155/2019/3690561

Cited by 34 publications

(27 citation statements)

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“…CCL2/CCR2 chemokine signaling was demonstrated to promote breast cancer progression by inducing angiogenesis 20 . Although previous studies reported that CCL2 could be transactivated by several transcriptional factors such as NF-κB, STAT3, STAT1, Twist1, and ETS1 40 , we confirmed in the present study that ETV5-activated STAT3 could enhance CCL2 transcription in CRC. Using an ELISA assay, we found that attenuation of VEGFA did not affect ETV5-mediated CCL2 secretion, and antiCCL2 treatment also did not influence ETV5-mediated VEGFA secretion in CRC cells.…”

Section: Discussionsupporting

confidence: 75%

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

et al. 2020

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In our previous study, ETV5 mediated-angiogenesis was demonstrated to be dependent upon the PDGF-BB/PDGFR-β/Src/STAT3/VEGFA pathway in colorectal cancer (CRC). However, the ability of ETV5 to affect the efficacy of anti-angiogenic therapy in CRC requires further investigation. Gene set enrichment analysis (GSEA) and a series of experiments were performed to identify the critical candidate gene involved in Bevacizumab resistance. Furthermore, the ability of treatment targeting the candidate gene to enhance Bevacizumab sensitivity in vitro and in vivo was investigated. Our results revealed that ETV5 directly bound to the VEGFA promoter to promote translation of VEGFA. However, according to in vitro and in vivo experiments, ETV5 unexpectedly accelerated antiVEGF therapy (Bevacizumab) resistance. GSEA and additional assays confirmed that ETV5 could promote angiogenesis by inducing the secretion of another tumor angiogenesis factor (CCL2) in CRC cells to facilitate Bevacizumab resistance. Mechanistically, ETV5 upregulated CCL2 by activating STAT3 to facilitate binding with the CCL2 promoter. ETV5 induced-VEGFA translation and CCL2 secretion were mutually independent mechanisms, that induced angiogenesis by activating the PI3K/AKT and p38/MAPK signaling pathways in human umbilical vein endothelial cells (HUVECs). In CRC tissues, ETV5 protein levels were positively associated with CD31, CCL2, and VEGFA protein expression. CRC patients possessing high expression of ETV5/VEGFA or ETV5/CCL2 exhibited a poorer prognosis compared to that of other patients. Combined antiCCL2 and antiVEGFA (Bevacizumab) treatment could inhibit tumor angiogenesis and growth more effectively than single treatments in CRCs with high expression of ETV5 (ETV5+ CRCs). In conclusion, our results not only revealed ETV5 as a novel biomarker for anti-angiogenic therapy, but also indicated a potential combined therapy strategy that involved in targeting of both CCL2 and VEGFA in ETV5+ CRC.

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Section: Discussionsupporting

confidence: 75%

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

et al. 2020

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“…15 It is proved that PIPKI facilitates PI3K-Akt-mTOR signaling pathway activation to increase STAT3 phosphorylation levels, thus triggering tumorassociated macrophage recruitment. 16 Another study reports that STAT3 is highly expressed in CRC and high STAT3 expression is markedly associated with a poor prognosis in patients with CRC. 17 Bioinformatics analysis (Starbase/TargetScans) showed that DICER1-AS1 could probably adsorb miR-296-5p, and miR-296-5p may target the 3ʹ UTR of STAT3 mRNA.…”

Section: Introductionmentioning

confidence: 99%

<p>DICER1-AS1 Promotes the Malignant Behaviors of Colorectal Cancer Cells by Regulating miR-296-5p/STAT3 Axis</p>

Ma¹,

Ma²,

Qin³

et al. 2020

CMAR

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Background: Long non-coding RNA (lncRNA) exerts a regulatory role in the occurrence and progression of tumors. This study aimed at probing into the function and mechanism of lncRNA DICER1 antisense RNA 1 (DICER1-AS1) in colorectal cancer (CRC). Methods: The expressions of DICER1-AS1, miR-296-5p and STAT3 mRNA were tested by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) assay was employed to detect cell proliferation, and Transwell was used to detect cell migration and invasion. In addition, the expressions of apoptosis-related proteins Bax and Bcl2 were detected by Western blot. Interactions between DICER1-AS1 and miR-296-5p, and miR-296-5p and STAT3 were predicted and determined by bioinformatics analysis, luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay. Results: The expressions of DICER1-AS1 and STAT3 mRNA were significantly upregulated while miR-296-5p expression was remarkably down-regulated in CRC tissues and cell lines. Over-expression of DICER1-AS1 or transfection of miR-296-5p inhibitors could promote the proliferation, migration and invasion and inhibit apoptosis of CRC cells, whereas knockdown of DICER1-AS1 or transfection of miR-296-5p mimics had the opposite effects. Additionally, DICER1-AS1 could down-regulate miR-296-5p expression via sponging it. DICER1-AS1 also enhanced the expression of STAT3, which was identified as a target gene of miR-296-5p. Conclusion: DICER1-AS1 acts as an oncogenic lncRNA in CRC via modulating miR-296-5p/STAT3 axis. Our results provide a new direction for the diagnosis and treatment of CRC.

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“…In the article titled “PIPKI γ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling” [ 1 ], the Acknowledgments section should read as follows:…”

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confidence: 99%

Corrigendum to “PIPKIγ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling”

Xue

Zhao

et al. 2020

Journal of Immunology Research

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PIPKIγ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling

Cited by 34 publications

References 50 publications

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

Targeting tumor cell-derived CCL2 as a strategy to overcome Bevacizumab resistance in ETV5+ colorectal cancer

<p>DICER1-AS1 Promotes the Malignant Behaviors of Colorectal Cancer Cells by Regulating miR-296-5p/STAT3 Axis</p>

Corrigendum to “PIPKIγ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling”

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