E2F1/SP3/STAT6 axis is required for IL-4-induced epithelial-mesenchymal transition of colorectal cancer cells

Chen, Jiaoe; Gong, Chaoju; Mao, Huiqin; Li, Zhaoyun; Fang, Zejun; Chen, Qiang; Lin, Min; Jiang, Xiang; Hu, Yifei; Wang, Wei; Zhang, Xiaomin; Chen, Xianjun; Li, Hongzhang

doi:10.3892/ijo.2018.4429

Cited by 57 publications

(60 citation statements)

References 37 publications

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“…4C ; P<0.001). Following examination of previous literature, it was noted that E2F1 serves a crucial role in CRC and is an important molecular regulator upstream of p21 ( 20 , 21 ). Therefore, it was hypothesized that E2F1 may participate in the regulation of p21 expression by CDCA3.…”

Section: Resultsmentioning

confidence: 99%

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

et al. 2018

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Dysregulated cell cycle progression serves a crucial role in tumor development. Cell division cycle- associated 3 (CDCA3) is considered a trigger of mitotic entry; it is an important part of the S phase kinase-associated protein 1/Cullin/F-box ubiquitin ligase complex and mediates the destruction of mitosis-inhibitory kinase wee1. However, little is known about the role of CDCA3 in cancer, particularly colorectal cancer (CRC). The present study aimed to explore the biological and clinical significance of CDCA3 in CRC growth and progression. CDCA3 expression was significantly associated with tumor progression and poor survival. Overexpression of CDCA3 increased proliferation in LoVo CRC cells, whereas CDCA3 knockdown in SW480 CRC cells led to decreased proliferation, in vitro and in vivo. Further mechanistic investigations demonstrated that reduced CDCA3 expression resulted in G1/S phase transition arrest, which was attributed to a significant accumulation of p21 in SW480 cells; conversely, increased CDCA3 expression promoted G1/S phase transition through decreased p21 accumulation in LoVo cells. It was also demonstrated that CDCA3 was able to regulate the expression of transcription factor E2F1, thereby repressing p21 expression. Taken together, these results suggested that overexpression of CDCA3 may serve a crucial role in tumor malignant potential and that CDCA3 may be used as a prognostic factor and a potential therapeutic target in CRC.

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Section: Resultsmentioning

confidence: 99%

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

et al. 2018

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“…The role of STAT6 in cancer has recently been studied; there are studies in colorectal cancer, prostate cancer, glioblastoma, gastric cancer, and breast cancer that indicate that STAT6 may have an important role in the growth, aggressiveness, resistance to apoptosis, epithelial to mesenchymal transition, and metastasis of cancer cells [ 145 , 146 , 147 , 148 , 149 ]. However, some research groups suggest that STAT6 is necessary to inhibit growth and to mediate apoptosis via IL-4 in melanoma, colorectal, and breast cancer cells [ 150 , 151 , 152 ].…”

Section: Jak/stat Pathway and Cervical Cancermentioning

confidence: 99%

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Gutiérrez‐Hoya

Soto‐Cruz²

2020

Cells

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The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

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“…Moreover, some reports have indicated that STAT6 overexpression plays a critical role in promoting EMT and aggressiveness of CRC through Zinc-finger E-box binding homeobox 1 (ZEB1) activation, which is currently considered as a factor associated with chemoresistance [56]. In line with this, we found that STAT6 regulates SNAI1, another typical marker of EMT, which has an important role in E-cadherin expression and that the levels of SNAI1 were inversely related with E-cadherin expression, as reported in esophageal cancer [47].…”

Section: Discussionmentioning

confidence: 99%

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

Mendoza

Sánchez-Barrera

Callejas

et al. 2020

IJMS

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Colorectal cancer (CRC) is one of the most widespread and deadly types of neoplasia around the world, where the inflammatory microenvironment has critical importance in the process of tumor growth, metastasis, and drug resistance. Despite its limited effectiveness, 5-fluorouracil (5-FU) is the main drug utilized for CRC treatment. The combination of 5-FU with other agents modestly increases its effectiveness in patients. Here, we evaluated the anti-inflammatory Trimethylglycine and the Signal transducer and activator of transcription (STAT6) inhibitor AS1517499, as possible adjuvants to 5-FU in already established cancers, using a model of colitis-associated colon cancer (CAC). We found that these adjuvant therapies induced a remarkable reduction of tumor growth when administrated together with 5-FU, correlating with a reduction in STAT6-phosphorylation. This reduction upgraded the effect of 5-FU by increasing both levels of apoptosis and markers of cell adhesion such as E-cadherin, whereas decreased epithelial–mesenchymal transition markers were associated with aggressive phenotypes and drug resistance, such as β-catenin nuclear translocation and Zinc finger protein SNAI1 (SNAI1). Additionally, Il-10, Tgf-β, and Il-17a, critical pro-tumorigenic cytokines, were downmodulated in the colon by these adjuvant therapies. In vitro assays on human colon cancer cells showed that Trimethylglycine also reduced STAT6-phosphorylation. Our study is relatively unique in focusing on the effects of the combined administration of AS1517499 and Trimethylglycine together with 5-FU on already established CAC which synergizes to markedly reduce the colon tumor load. Together, these data point to STAT6 as a valuable target for adjuvant therapy in colon cancer.

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E2F1/SP3/STAT6 axis is required for IL-4-induced epithelial-mesenchymal transition of colorectal cancer cells

Cited by 57 publications

References 37 publications

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

Use of STAT6 Phosphorylation Inhibitor and Trimethylglycine as New Adjuvant Therapies for 5-Fluorouracil in Colitis-Associated Tumorigenesis

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