Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas

Cheng, Shaomei; Guo, Jingyan; Yang, Qing; Yang, Xijia

doi:10.1007/s12032-015-0494-1

Cited by 36 publications

(34 citation statements)

References 25 publications

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“…CRKL amplification was previously observed in non‐small cell lung and gastric cancers, strongly suggesting that CRKL is an oncogene in multiple cancers. Consistent with the data from previous papers that CRKL expression correlates with poor prognosis, Prognoscan, a publicly available database, indicates that high expression of CRKL may serve as a poor prognostic factor for liposarcoma and lung adenocarcinoma patients (Fig. S9).…”

Section: Discussionsupporting

confidence: 89%

CRKL oncogene is downregulated by p53 through miR‐200s

et al. 2015

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Tumor suppressive miRNAs that target oncogenes are frequently downregulated in cancers, and this downregulation leads to oncogene pathway activation. Thus, tumor suppressive miRNAs and their target oncogenes have been proposed as useful targets in cancer treatment. miR-200 family downregulation has been reported in cancer progression and metastasis. The miR-200 family consists of two gene clusters, miR-200b/200a/429 and miR-200c/141, which are located on human chromosomes 1 and 12, respectively. Here, we identified that p53 response elements are located around both clusters of the miR-200 family and confirmed that miR-200s are transcriptional targets of the p53 family. In silico analyses of miRNA targets established the CRKL oncogene as a potential target for miR-200b/200c/429. Moreover, miR-200b/200c/429 inhibited CRKL mRNA and protein expression by directly targeting its 3′-UTR region. Importantly, endogenous CRKL expression was decreased in cancer cells through the introduction of p53 family and endogenous p53 activation. Moreover, the downregulation of CRKL by siRNA inhibited cancer cell growth. The Oncomine database demonstrates that CRKL is overexpressed in a subset of cancer types. Furthermore, CRKL is significantly overexpressed in primary breast cancer tissues harboring mutant TP53 . Our results demonstrate that the p53 target miR-200b/200c/429 miRNAs are negative regulators of the CRKL oncogene.

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Section: Discussionsupporting

confidence: 89%

CRKL oncogene is downregulated by p53 through miR‐200s

et al. 2015

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“…Accumulating evidence has been reported and suggested that dysfunction of CRKL as a key factor in variety of human diseases, including inflammation and carcinomas [18–20]. In our previous study, we also validated CRKL as a promoter in GC, induces GC cells proliferation and motility.…”

Section: Discussionsupporting

confidence: 63%

SLC7A5 Functions as a Downstream Target Modulated by CRKL in Metastasis Process of Gastric Cancer SGC-7901 Cells

Wang

Fei

et al. 2016

PLoS ONE

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SLC7A5, who is also named LAT-1, has been validated as a promoter regulated by miRNA-126 in our previous research for gastric cancer cells. However, the mechanisms driving SLC7A5 to affect the bio-function of gastric cancer cells are unclear, remaining us lots of to elucidate. The aim of this study is to investigate the regulating effect of CRKL, one of the critical genes involving with gastric cancer progression, on SLC7A5 expression. By studying the gastric cancer cell lines and clinical pathological specimens, we found that the expression of SLC7A5 was significantly correlated to CRKL. By depleting CRKL in gastric cancer SGC-7901 cells, the SLC7A5 expression was impaired, and the invasion and migration of SGC-7901 cells were suppressed. Ectopic expression of SLC7A5 could drastically rescue the phenotypes induced by CRKL depletion in this study. Accordingly, we conclude that SLC7A5 functions as a promoter in gastric cancer metastasis, and CRKL could be one of its regulators modulating the expression of SLC7A5 and consequentially affect the metastatic feature of SGC-7901 cells. The findings in this study indicate a regulation relationship between CRKL and SLC7A5, and provide useful evidence for gastric cancer therapeutic strategies.

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“…CCR7 is expressed by gastric cancer cells, with higher levels of CCR7 expression associated with lymph node metastasis, higher stage tumor, and poor overall survival. Treatment of human gastric cancer cells with CCL19 induced the expression of MMP-9 and decreased levels of E-cadherin, consistent with a shift towards a pro-metastatic phenotype (Cheng, Guo, Yang, & Yang, 2015). In ovarian cancer, CCR7 + tumor status was also correlated with advanced disease stage and with lymph node metastasis, and these clinical parameters were linked to increased expression of MMP-9 and N-cadherin (Cheng et al, 2014) that were subsequently determined to be dependent upon CCL19 signaling (Cheng et al, 2015).…”

Section: Cues For Tls Developmentmentioning

confidence: 74%

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

Weinstein

Storkus

2015

Advances in Cancer Research

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The inflammatory status of the tumor microenvironment (TME) has been heavily investigated in recent years. Chemokine and cytokine signaling pathways such as CCR7, CXCR5, lymphotoxin, and IL-36, which are involved in the generation of secondary lymphoid organs and effector immune responses, are now recognized as having value both as prognostic factors and as immunomodulatory therapeutics in the context of cancer. Furthermore, when produced in the TME, these mediators have been shown to promote the recruitment of immune cells, including T cells, B cells, dendritic cells (DC), and other specialized immune cell subsets such as follicular dendritic cells (FDC) and T follicular helper (Tfh) cells, in association with the formation of “tertiary” lymphoid structures (TLS) within or adjacent to sites of disease. Although TLS are composed of a heterogeneous collection of immune cell types, whose composition differs based on cancer subtype, the qualitative presence of TLS has been shown to represent a biomarker of good prognosis for cancer patients. A comprehensive understanding of the role each of these pathways plays within the TME may support the rational design of future immunotherapies to selectively promote/bolster TLS formation and function, leading to improved clinical outcomes across the vast range of solid cancer types.

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Crk-like adapter protein regulates CCL19/CCR7-mediated epithelial-to-mesenchymal transition via ERK signaling pathway in epithelial ovarian carcinomas

Cited by 36 publications

References 25 publications

CRKL oncogene is downregulated by p53 through miR‐200s

CRKL oncogene is downregulated by p53 through miR‐200s

SLC7A5 Functions as a Downstream Target Modulated by CRKL in Metastasis Process of Gastric Cancer SGC-7901 Cells

Therapeutic Lymphoid Organogenesis in the Tumor Microenvironment

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