Upregulation of FBXW7 Suppresses Renal Cancer Metastasis and Epithelial Mesenchymal Transition

Cai, Yangke; Zhang, Meng; Qiu, Xiaoyu; Wang, Bingwei; Fu, Yu; Zeng, Jun; Bai, Jian; Yang, Guosheng

doi:10.1155/2017/8276939

Cited by 17 publications

(20 citation statements)

References 20 publications

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“…The present study attempted to examine how miR-27a was involved in breast cancer cell migration regulation. The expression of FBXW7 in MDA-MB-231 cells with silenced miR-27a was detected, due to the important functions of EMT regulation in cancer cells ( 20 , 21 ). The data revealed that the reduction of miR-27a increased FBXW7 expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, FBXW7 serves critical roles in regulating the metastasis of cancer cells by targeting the EMT process. In renal cancer cells, the upregulation of FBXW7 is able to effectively suppress metastasis by inhibiting EMT ( 20 ). FBXW7 is also able to regulate EMT, in part through the Ras homolog gene family member A signaling pathway in gastric cancer ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner

et al. 2018

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Increasingly, evidence has revealed that aberrant microRNA (miRNA) expression is involved in breast cancer carcinogenesis and further progression, including metastasis. miRNA (miR)-27a was previously identified to be abnormally expressed and to serve pro-oncogenic functions in multiple human cancer types, including breast cancer. However, its functions and underlying mechanisms in breast cancer remain poorly understood. In the present study, it was demonstrated that miR-27a was significantly upregulated in breast cancer tissues and cell lines compared with their normal counterparts. Overexpression of miR-27a resulted in enhanced cell migration by inducing epithelial-to-mesenchymal transition, while its knockdown effectively reversed these cellular events. The present study additionally confirmed for the first time, to the best of our knowledge, that F-box and WD repeat domain containing 7 (FBXW7) is a downstream target gene of miR-27a in human breast cancer cells. FBXW7 is underexpressed in breast cancer tissues and cell lines, and is an independent positive factor for the overall survival rate of patients with breast cancer. Notably, the ectopic expression of FBXW7 may effectively suppress the epithelial-to-mesenchymal transition and migratory activity of breast cancer cells, in addition to reversing the cell migration mediated by miR-27a. Altogether, the results of the present study indicated the important function of miR-27a in regulating the metastasis of breast cancer in a FBXW7-dependent manner, and provide evidence for the potential application of miR-27a in breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner

et al. 2018

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“…FBW7 is directly involved in MMP-2, −9 and −13 mediated migration and invasion as a result of regulating expression of these metalloproteases (42). To determine if MMP-9 expression contributed to sT induced cell migration, initial assessments to validate whether MCV sT induces MMP-9 expression was performed.…”

Section: Resultsmentioning

confidence: 99%

“…Studies have shown MMP-9 exists in several forms; a monomeric pro form (∼92 kDa), a disulfide-bonded homodimeric (∼220 kDa) form and multiple active forms (∼67 and 82 kDa) (44, 45). The active and dimeric forms of MMP-9 play a role in the invasive and migratory phenotypes of cancer cells (42, 44, 46). MCV sT WT expression induced upregulation of dimer, pro and active forms of MMP-9, while MMP-9 protein levels upon MCV sT LSDm expression were comparable to vector control confirming that MCV sT upregulation of MMP-9 is LSD dependent.…”

Section: Resultsmentioning

confidence: 99%

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

Nwogu

Ortiz

Whitehouse³

et al. 2020

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46Merkel cell polyomavirus (MCV) small T antigen (sT) is the main oncoprotein for the 47 development of Merkel cell carcinoma (MCC). MCC is a rare, clinically aggressive 48 neuroendocrine tumor of the skin with a high propensity for local, regional, and distant 49 spread. The expression of matrix metalloproteinase (MMP)-9 has been implicated as 50 playing an important role in cell invasion and metastasis in many human cancers. 51Previously, MCV sT has been shown to increase the cell migration and invasiveness of 52 MCC cells through the transcriptional activation of the sheddase molecule, ADAM 10 (A 53 disintergrin and metalloprotease domain-containing protein 10). In this study, we show 54 that MCV sT protein stimulates epithelial-mesenchymal transition (EMT) gene 55 expression, including MMP-9. This effect is dependent on the presence of the large 56 stabilization domain (LSD), which is known to be responsible for cell transformation 57 through targeting of promiscuous E3 ligases, including FBW7, a known MMP-9 58 regulator. Chemical treatments of MMP-9 markedly inhibited sT-induced cell migration 59 and invasion. These results suggest that sT contributes to the activation of MMP-9 as a 60 result of FBW7 targeting, and increases the invasive potential of cells, which can be 61 used for a targeted therapeutic intervention. 62 63 IMPORTANCE 64Merkel cell carcinoma (MCC) is the most aggressive cutaneous tumor without clearly 65 defined treatment. Although MCC has high propensity for metastasis, little is known about 66 the underlying mechanisms that drive MCC invasion and metastatic progression. MMP-9 67 has shown to play a detrimental role in many metastatic human cancers, including 68 melanoma and other non-melanoma skin cancers. Our study discovers that MCV sT-69 mediated MMP-9 activation is driven through the LSD, a known E3 ligase targeting 70 domain, in MCC. MMP-9 may serve as the biochemical culprit to target and develop a 71 novel approach for the treatment of metastatic MCC. 72 5333. Kaae J, Hansen AV, Biggar RJ, Boyd HA, Moore PS, Wohlfahrt J, Melbye M. 534

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“…A previous study reported that melanoma-associated antigen 1 interacts with FBXW7 to regulate the ubiquitin ligase-mediated turnover of Notch1 intracellular domain 1 in breast and ovarian cancer cells (42). FBXW7 upregulation also suppresses metastasis and epithelial mesenchymal transition in RCC (43). However, the biological function and underlying mechanism of FBXW7 on miRNAs remain unknown in RCC.…”

Section: Discussionmentioning

confidence: 99%

Cell proliferation is induced in renal cell carcinoma through miR‑92a‑3p upregulation by targeting FBXW7

et al. 2020

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Renal cell carcinoma (RCC) is the most common type of kidney cancer whose incidence has gradually increased worldwide. MicroRNAs (miRNAs) represent a type of short endogenous non-coding RNA containing approximately 22 nucleotides, which are capable of regulating mRNAs at the post-transcriptional level in human cells. miRNAs have been demonstrated to mediate gene expression by influencing important regulatory genes. Accumulating evidence indicates that certain miRNAs are involved in RCC development. The present study investigated the underlying mechanism and functional role of miR-92a-3p in RCC cells using reverse transcription-quantitative polymerase chain reaction, western blotting, 3' UTR luciferase assay, cell proliferation assay and soft agar assay. The results demonstrated that miR-92a-3p expression level is significantly upregulated in RCC tissues and cell lines; however, F-box and WD repeat domain containing 7 (FBXW7) expression level was significantly downregulated in RCC tissues and cell lines. Subsequently, whether FBXW7 could be considered as a direct target of miR-92a-3p in RCC cells was investigated. The results demonstrated that miR-92a-3p overexpression significantly promoted RCC cell proliferation and colony formation. Conversely, miR-92a-3p downregulation significantly inhibited RCC cell proliferation and colony formation. In addition, FBXW7 knockdown significantly enhanced RCC cell proliferation and colony formation. Conversely, FBXW7 overexpression significantly inhibited RCC cell proliferation and colony formation. Collectively, these results demonstrated that miR-92a-3p/FBXW7 pathway may represent a novel strategy and therapeutic target for RCC.

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Upregulation of FBXW7 Suppresses Renal Cancer Metastasis and Epithelial Mesenchymal Transition

Cited by 17 publications

References 20 publications

miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner

miR‑27a promotes human breast cancer cell migration by inducing EMT in a FBXW7‑dependent manner

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

Cell proliferation is induced in renal cell carcinoma through miR‑92a‑3p upregulation by targeting FBXW7

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