Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT

He, Zhenyu; Wu, San Gang; Peng, Fang; Zhang, Qun; Luo, Ying; Chen, Ming; Bao, Yong

doi:10.1016/j.tranon.2016.10.004

Cited by 46 publications

(50 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies indicated that the overexpression of RFC3 promotes breast cancer metastasis and MCF-7 cell proliferation, and is associated with poor prognosis via the epithelial–mesenchymal transition, while the knockdown of RFC3 expression can inhibit MCF-7 cell proliferation and invasion. 19 , 20 Consistent with these conclusions, our findings showed that the downregulation of RFC3 levels with small interfering hsa_circ_0011946 resulted in the inhibition of migration and invasion in MCF-7 cells. Breast cancer patients with high RFC3 levels have a higher risk of distant metastases, 19 thus RFC3 might be an oncogene and might serve as a therapeutic target for breast cancer.…”

Section: Discussionsupporting

confidence: 87%

“… 13 , 14 RFC subunit 3 (RFC3) is one of the small subunits on the RFC complex and was originally purified from HeLa cells and shown to be essential for the in vitro replication of Simian virus 40. 14 In recent years, the various roles of RFC3 have been increasingly illuminated in studies of malignancies, including hepatocellular carcinoma, 15 ovarian carcinoma, 16 esophageal adenocarcinoma, 17 colorectal cancer, 18 and breast cancer, 19 , 20 suggesting that RFC3 may be a potential oncogenic gene involved in tumorigenesis. However, it is not clear how RFC3 regulates the progression of breast cancer when combined with circRNAs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3

Zhou¹,

Zhang²,

Peng³

et al. 2018

CMAR

Self Cite

View full text Add to dashboard Cite

IntroductionAlthough some circRNAs have been found to regulate the progression of malignancies, their functions and coupled molecular mechanisms are still unclear. In our study, we sought to assess the underlying molecular mechanisms of circRNAs in breast cancer and therefore explored the differentially expressed circRNAs and co-expression networks, followed by in vitro experiments.Materials and methodsHigh-throughput RNA sequencing was performed to obtain an unbiased profile of circRNA expression. CircRNA-miRNA-mRNA co-expression networks were predicted, and sequence analyses were carried out. The MTT, transwell migration and invasion assay was conducted in Michigan Cancer Foundation-7 cells that had been transfected with si-circRNA and si-negative control (si-NC).ResultsA total of 152 circRNAs were differentially expressed in breast cancer tissues, among which 85 were upregulated and 67 downregulated. Out of these, hsa_circ_0011946 was selected and the subsequent bioinformatics analysis predicted that hsa_circ_0011946 sponging miR-26a/b directly targeted replication factor C subunit 3 (RFC3) and that its knockdown could inhibit RFC3 mRNA and protein expression. Furthermore, hsa_circ_0011946 loss-of-function significantly suppressed the migration and invasion of Michigan Cancer Foundation-7 cells.ConclusionTogether, these results indicate that hsa_circ_0011946 and RFC3 comprise a novel pathway involved in the progression of breast cancer.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3

Zhou¹,

Zhang²,

Peng³

et al. 2018

CMAR

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, PCNA is a well‐established proliferation marker in some types of cancer . RFC3 is associated with proliferation activity of breast cancer cells or poor prognosis in ovarian cancer patients . Overexpression of FEN1 has been associated with enhanced cancer cell proliferation or poor clinical outcome in gastric, breast, ovarian and non‐small‐cell lung cancer .…”

Section: Discussionmentioning

confidence: 99%

HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells

et al. 2018

View full text Add to dashboard Cite

Heterogeneous nuclear ribonucleoprotein L‐like (HNRNPLL), an RNA‐binding protein that regulates alternative splicing of pre‐mRNA, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here, we show that HNRNPLL promotes cell cycle progression and, hence, proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed threefold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication‐related genes by HNRNPLL overexpression. Among 13 genes detected in the DNA replication pathway, PCNA,RFC3 and FEN1 showed reproducible upregulation by HNRNPLL overexpression both at mRNA and at protein levels in SW480 and HT29 cells. Importantly, knockdown of any of these genes alone suppressed the proliferation‐promoting effect induced by HNRNPLL overexpression. RNA‐immunoprecipitation assay presented a binding of FLAG‐tagged HNRNPLL to mRNA of these genes, and HNRNPLL overexpression significantly suppressed the downregulation of these genes during 12 h of actinomycin D treatment, suggesting a role of HNRNPLL in mRNA stability. Finally, analysis of a public RNA sequencing dataset of clinical samples suggested a link between overexpression of HNRNPLL and that of PCNA,RFC3 and FEN1. This link was further supported by immunohistochemistry of colorectal cancer clinical samples, whereas expression of CDKN1A, which is known to inhibit the cooperative function of PCNA, RFC3 and FEN1, was negatively associated with HNRNPLL expression. These results indicate that HNRNPLL stabilizes mRNA encoding regulators of DNA replication and promotes colorectal cancer cell proliferation.

show abstract

“…The MCM complex forms the core of the DNA replicative helicase and, interestingly, is associated with cisplatin resistance [79]. Increased RFC expression has been shown to be associated with epithelialmesenchymal transition and poor outcomes in both lung and breast cancer [80]. Other complexes we identified, such as the BRCC and the Condesin complexes, have been linked to DNA repair in cancer [81,82].…”

Section: Discussionmentioning

confidence: 95%

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

Shrestha

Fernández

Dawson

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates. As such, there is a pressing need to develop more effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use a multiomics approach to interrogate a collection of LGSOC patient-derived cell lines to elucidate novel biomarkers and therapeutic vulnerabilities.Methods: Fourteen LGSOC cell lines were interrogated using whole exome sequencing, RNA sequencing, and mass spectrometry-based proteomics. Somatic mutation, copy-number aberrations, gene and protein expression were analyzed and integrated using different computational approaches.LGSOC cell line data was compared to publicly available LGSOC tumor data (AACR GENIE cohort), and also used for predictive biomarker identification of MEK inhibitor (MEKi) efficacy. Protein interaction databases were evaluated to identify novel therapeutic targets. Results: KRAS mutations were exclusively found in MEKi-sensitive and NRAS mutations mostly in MEKiresistant cell lines. Analysis of COSMIC mutational signatures revealed distinct patterns of nucleotide substitution mutations in MEKi-sensitive and MEKi-resistant cell lines. Deletions of CDKN2A/B and MTAP genes (chromosome 9p21) were much more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. For in-vitro MEKi efficacy prediction, proteomic data provided better discrimination than gene expression data. Condensin, MCM, and RFC protein complexes were identified as potential treatment targets in MEKi-resistant cell lines.Conclusions: Our LGSOC cell lines are representative models of the most common molecular aberrations found in LGSOC tumors. This study highlights the importance of using proteomic data in multiomics assessment of drug prediction and identification of potential therapeutic targets. CDKN2A/B and MTAP deficiency offer an opportunity to find synthetically lethal candidates for novel treatments.Multiomics approaches are crucial to improving our understanding of the molecular aberrations inLGSOC, establishing effective drug prediction programs and identifying novel therapeutic targets inLGSOC. BackgroundLow-grade serous ovarian carcinoma (LGSOC) is a rare subtype of epithelial ovarian cancer with a poor prognosis. Women with LGSOC are usually diagnosed with advanced-stage disease and only 10-20% are alive 10 years after diagnosis [1,2]. Research on LGSOC is challenging due to its low prevalence, uncertain etiology, and the limited availability of research models. However, in the last 5-10 years investigators have elucidated many key genomic aberrations, leading to major advancements in the molecular characterization and classification of LGSOC [3,4]. In contrast to other ovarian cancer subtypes, LGSOC are genetically characterized by high frequency of oncogenic mutations in KRAS, NRAS, and BRAF (20-40%, 7-26%, 5-33%, respectively) [5-7], a very low prevalence of TP53 mutatio...

show abstract

Up-Regulation of RFC3 Promotes Triple Negative Breast Cancer Metastasis and is Associated With Poor Prognosis Via EMT

Cited by 46 publications

References 33 publications

Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3

Downregulation of hsa_circ_0011946 suppresses the migration and invasion of the breast cancer cell line MCF-7 by targeting RFC3

HNRNPLL stabilizes mRNA for DNA replication proteins and promotes cell cycle progression in colorectal cancer cells

Multiomics Characterization of Potential Therapeutic Vulnerabilities in Low-grade Serous Ovarian Carcinoma

Contact Info

Product

Resources

About