E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

Fang, Zejun; Gong, Chaoju; Liu, Hong; Zhang, Xiaomin; Mei, Lingming; Song, Mintao; Qiu, Lanlan; Luo, Shuchai; Zhu, Zhihua; Zhang, Ronghui; Gu, Hongqian; Chen, Xiang

doi:10.1016/j.bbrc.2015.06.103

Cited by 55 publications

(40 citation statements)

References 29 publications

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“…RRM2 is known to function as a tumor driver during carcinogenesis and high expressed in esophageal cancer, gastric cancer, colon cancer, and hepatocellular cancer [21][22][23][24][25]. This study also showed that RRM2 was higher expressed in most PTC samples and seemed to be more intensively stained in UTC tissues.…”

Section: Discussionsupporting

confidence: 58%

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

et al. 2015

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Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

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Section: Discussionsupporting

confidence: 58%

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

et al. 2015

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“…E2F1 upregulation in mammary cell lines causes carcinogenesis and aggressive distant metastasis in multiple cancers (34)(35)(36). E2F1 may enhance metastatic behavior in melanomas by directly binding with VEGFC and the corresponding receptor VEGFR-3 for transactivation (37).…”

Section: Discussionmentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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“…E2F1 overexpression was reported to be correlated with LNM and distant metastasis in CRC [22]. In addition, E2F1 and RAP2B were reported to promote progression and metastasis of lung cancer and their expressions was downregulated by miR-342-3p in lung cancer [26, 28].…”

Section: Discussionmentioning

confidence: 99%

Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer

Jung

Yim

et al. 2016

Oncotarget

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Accurate prediction of regional lymph node metastasis (LNM) in endoscopically resected T1-stage colorectal cancers (CRCs) can reduce unnecessary surgeries. To identify miRNA markers that can predict LNM in T1-stage CRCs, the study was conducted in two phases; (I) miRNA classifier construction by miRNA-array and quantitative reverse transcription PCR (qRT-PCR) using 36 T1-stage CRC samples; (II) miRNA classifier validation in an independent set of 20 T1-stage CRC samples. The expression of potential downstream target genes of miRNAs was assessed by immunohistochemistry. In the discovery analysis by miRNA microarray, expression of 66 miRNAs were significantly different between LNM-positive and negative CRCs. After qRT-PCR validation, 11 miRNAs were consistently significant in the combined classifier construction set. Among them, miR-342-3p was the most significant one (P=4.3×10−4). Through logistic regression analysis, we developed a three-miRNA classifier (miR-342-3p, miR-361-3p, and miR-3621) for predicting LNM in T1-stage CRCs, yielding the area under the curve of 0.947 (94% sensitivity, 85% specificity and 89% accuracy). The discriminative ability of this system was consistently reliable in the independent validation set (83% sensitivity, 64% specificity and 70% of accuracy). Of the potential downstream targets of the three-miRNAs, expressions of E2F1, RAP2B, and AKT1 were significantly associated with LNM. In conclusion, this classifier can predict LNM more accurately than conventional pathologic criteria and our study results may be helpful to avoid unnecessary bowel surgery after endoscopic resection in early CRC.

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E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

Cited by 55 publications

References 29 publications

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Predictive microRNAs for lymph node metastasis in endoscopically resectable submucosal colorectal cancer

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