Gene Summary

Gene:CDKN1C; cyclin dependent kinase inhibitor 1C
Aliases: BWS, WBS, p57, BWCR, KIP2, p57Kip2
Summary:This gene is imprinted, with preferential expression of the maternal allele. The encoded protein is a tight-binding, strong inhibitor of several G1 cyclin/Cdk complexes and a negative regulator of cell proliferation. Mutations in this gene are implicated in sporadic cancers and Beckwith-Wiedemann syndorome, suggesting that this gene is a tumor suppressor candidate. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 1C
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CDKN1C (cancer-related)

Herreño AM, Ramírez AC, Chaparro VP, et al.
Role of RUNX2 transcription factor in epithelial mesenchymal transition in non-small cell lung cancer lung cancer: Epigenetic control of the RUNX2 P1 promoter.
Tumour Biol. 2019; 41(5):1010428319851014 [PubMed] Related Publications
Lung cancer has a high mortality rate in men and women worldwide. Approximately 15% of diagnosed patients with this type of cancer do not exceed the 5-year survival rate. Unfortunately, diagnosis is established in advanced stages, where other tissues or organs can be affected. In recent years, lineage-specific transcription factors have been associated with a variety of cancers. One such transcription factor possibly regulating cancer is RUNX2, the master gene of early and late osteogenesis. In thyroid and prostate cancer, it has been reported that RUNX2 regulates expression of genes important in tumor cell migration and invasion. In this study, we report on RUNX2/ p57 overexpression in 16 patients with primary non-small cell lung cancer and/or metastatic lung cancer associated with H3K27Ac at P1 gene promoter region. In some patients, H3K4Me3 enrichment was also detected, in addition to WDR5, MLL2, MLL4, and UTX enzyme recruitment, members of the COMPASS-LIKE complex. Moreover, transforming growth factor-β induced RUNX2/ p57 overexpression and specific RUNX2 knockdown supported a role for RUNX2 in epithelial mesenchymal transition, which was demonstrated through loss of function assays in adenocarcinoma A549 lung cancer cell line. Furthermore, RUNX2 increased expression of epithelial mesenchymal transition genes VIMENTIN, TWIST1, and SNAIL1, which reflected increased migratory capacity in lung adenocarcinoma cells.

Sale MJ, Balmanno K, Saxena J, et al.
MEK1/2 inhibitor withdrawal reverses acquired resistance driven by BRAF
Nat Commun. 2019; 10(1):2030 [PubMed] Free Access to Full Article Related Publications
Acquired resistance to MEK1/2 inhibitors (MEKi) arises through amplification of BRAF

Park YL, Ha SY, Park SY, et al.
Reversine induces cell cycle arrest and apoptosis via upregulation of the Fas and DR5 signaling pathways in human colorectal cancer cells.
Int J Oncol. 2019; 54(5):1875-1883 [PubMed] Related Publications
Reversine, a 2,6‑diamino‑substituted purine analogue, has been reported to be effective in tumor suppression via induction of cell growth arrest and apoptosis of cancer cells. However, it remains unclear whether reversine exerts anticancer effects on human colorectal cancer cells. In the present study, in vitro experiments were conducted to investigate the anticancer properties of reversine in human colorectal cancer cells. The effect of reversine on human colorectal cancer cell lines, SW480 and HCT‑116, was examined using a WST‑1 cell viability assay, fluorescence microscopy, flow cytometry, DNA fragmentation, small interfering RNA (siRNA) and western blotting. Reversine treatment demonstrated cytotoxic activity in human colorectal cancer cells. It also induced apoptosis by activating poly(ADP‑ribose) polymerase, caspase‑3, ‑7 and ‑8, and increasing the levels of the pro‑apoptotic protein second mitochondria‑derived activator of caspase/direct inhibitor of apoptosis‑binding protein with low pI. The pan‑caspase inhibitor Z‑VAD‑FMK attenuated these reversine‑induced apoptotic effects on human colorectal cancer cells. Additionally, reversine treatment induced cell cycle arrest in the subG1 and G2/M phases via increase in levels of p21, p27 and p57, and decrease in cyclin D1 levels. The expression of Fas and death receptor 5 (DR5) signaling proteins in SW480 and HCT116 cells was upregulated by reversine treatment. Reversine‑induced apoptosis and cell cycle arrest were suppressed by inhibition of Fas and DR5 expression via siRNA. In conclusion, Reversine treatment suppressed tumor progression by the inhibition of cell proliferation, induction of cell cycle arrest and induction of apoptosis via upregulation of the Fas and DR5 signaling pathways in human colorectal cancer cells. The present study indicated that reversine may be used as a novel anticancer agent in human colorectal cancer.

Zeng CX, Fu SB, Feng WS, et al.
TCF19 enhances cell proliferation in hepatocellular carcinoma by activating the ATK/FOXO1 signaling pathway.
Neoplasma. 2019; 66(1):46-53 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies because of its complexity, high metastasis, recurrence and limited treatment options. Reports state that transcription factor 19 (TCF19) is related to the susceptibility to chronic HBV infection and that it strongly increases the risk of HCC occurrence, but its molecular mechanisms remain unknown. This study analyzed the datasets and confirmed that TCF19 is significantly increased in HCC cell lines and tissues. MTT and colony formation assay revealed that TCF19 over-expression enhances cell proliferation and tumorigenesis. Flow cytometry assay then determined that TCF over-expression helps HCC cell G1/S phase transition, and further research showed that TCF19 up-regulation inhibits p57Kip2, p21Cip1 and p27Kip1 cell cycle suppressors, enhances the expression of cyclin D1 expression and simulates retinoblastoma (Rb), FOXO1 and AKT phosphorylation. In addition, AKT and FOXO1 inhibitors suppress the TCF19 effect on cell proliferation. This demonstrates that AKT/FOXO1 signaling is essential for TCF19 influence on HCC progression, and our combined results suggest that crucial links between TCF19 and HCC can provide a novel target for hepatocellular carcinoma treatment.

Ronnett BM
Hydatidiform Moles: Ancillary Techniques to Refine Diagnosis.
Arch Pathol Lab Med. 2018; 142(12):1485-1502 [PubMed] Related Publications

Basu P, Maier C
Phytoestrogens and breast cancer: In vitro anticancer activities of isoflavones, lignans, coumestans, stilbenes and their analogs and derivatives.
Biomed Pharmacother. 2018; 107:1648-1666 [PubMed] Related Publications
Breast cancer is one of the leading causes of cancer-related morbidity and mortality among women worldwide. Phytoestrogens, plant-derived polyphenols that structurally and functionally mimic 17β-estradiol, the mammalian estrogen hormone, are known to modulate multiple molecular targets in breast cancer cells. The structural and chemical similarities to estradiol enable phytoestrogens to exert estrogenic or antiestrogenic activities by binding to the estrogen receptors. Although phytoestrogens have low affinity for estrogen receptors, they are able to compete with 17β-estradiol for the ligand-binding domain of the receptors. Phytoestrogens trigger epigenomic effects that could be beneficial in breast cancer prevention and/or treatment. Few studies have focused on the cytotoxic and structure-activity relationships of phytoestrogen analogs and derivatives with more effective anticancer properties than their corresponding parent compounds. Phytoestrogens and their analogs and derivatives bind to estrogen receptors, with a preferential affinity for ERβ, and inhibit the growth promoting activity of ERα. These bioactive compounds also exert growth inhibitory effects through various cell signaling pathways. At the level of cell cycle, they inhibit the expression of oncogenic cyclin D1, increase the expression of cyclin-dependent kinase inhibitors (p21, p27, and p57) and tumor suppressor genes (APC, ATM, PTEN, SERPINB5). Phytoestrogens and their analogs and derivatives mediate their effects on breast cancer by inhibiting estrogen synthesis and metabolism, as well as exerting antiangiogenic, antimetastatic, and epigenetic effects. Furthermore, these bioactive compounds reverse multi-drug resistance. This review offers a comprehensive summary of current literature and future perspectives on the in vitro molecular mechanisms of the anticancer activities of phytoestrogens and their analogs and derivatives on breast cancer.

Gu W, Zhang E, Song L, et al.
Long noncoding RNA HOXD-AS1 aggravates osteosarcoma carcinogenesis through epigenetically inhibiting p57 via EZH2.
Biomed Pharmacother. 2018; 106:890-895 [PubMed] Related Publications
Osteosarcoma is the most common primary malignant bone tumor and long non-coding RNAs (lncRNAs) have been proved to epigenetically regulate the oncogenesis of osteosarcoma. In this research, we investigate the role of lncRNA HOXD-AS1 on the osteosarcoma oncogenesis. Results revealed that HOXD-AS1 expression level was significantly up-regulated in osteosarcoma tissue and cells, moreover, the aberrant overexpression predicted the poor prognosis of osteosarcoma patients. Loss-of-functional experiments indicated that HOXD-AS1 silencing inhibited the osteosarcoma cells proliferation and induced G1/G0 phase arrest in vitro, and repressed tumor cell growth in vivo. Mechanistic investigations showed that HOXD-AS1 epigenetically repressed p57 through recruiting enhancer of zeste homolog 2 (EZH2) to the promoter of p57. Rescue experiments revealed that p57 could recover the oncogenic role of HOXD-AS1 on osteosarcoma. In conclusion, our study confirmed that HOXD-AS1 could interact with EZH2, and then repress p57 expression, to aggravate osteosarcoma oncogenesis. which provide new idea for the osteosarcoma tumorigenesis.

Wang Y, Wang Y, Liu S, et al.
Upregulation of EID3 sensitizes breast cancer cells to ionizing radiation-induced cellular senescence.
Biomed Pharmacother. 2018; 107:606-614 [PubMed] Related Publications
Previous studies have shown that BMS-345541 (BMS, a specific IκB kinase β inhibitor) sensitized various tumor cells including MCF-7 breast cancer cells to ionizing radiation (IR). However, the mechanisms of BMS action are unknown. Since the expression of E1A-like inhibitor of differentiation 3 (EID3) was highly upregulated in MCF-7 cells after BMS treatment, we investigated the role of EID3 in the response of MCF-7 cells to IR. We found that BMS induced EID3 expression in MCF-7 cells in a time- and dose-dependent manner. Knockdown of EID3 by specific shRNA attenuated BMS-induced radiosensitization in MCF-7 cells. In contrast, induction of EID3 expression in an inducible EID3 expressing MCF-7 cell line with doxycycline sensitized the cells to IR. EID3-mediated sensitization of MCF-7 cells to IR was not attributed to an increase in apoptosis. Instead, EID3-expressing MCF-7 cells exhibited significantly higher levels of senescence associated β-galactosidase (SA-β-gal) activity and higher levels of p21 and p57 than EID3-MCF-7 cells without induction of EID3 after exposure to IR. Similar findings were observed when EID3-expressing MCF-7 cells were treated with etoposide, a topoisomerase II inhibitor. Taken together, our findings reveal a novel function of EID3 and suggest that the induction of EID3 by BMS may be exploited as a new strategy to sensitize breast cancer cells to IR and chemotherapy by inducing cancer cell senescence.

Zheng Q, Fan H, Meng Z, et al.
Histone demethylase KDM2B promotes triple negative breast cancer proliferation by suppressing p15INK4B, p16INK4A, and p57KIP2 transcription.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(9):897-904 [PubMed] Related Publications
H3K4me3 and H3K36me2 histone demethylase KDM2B is an epigenetic regulatory factor involved in cell proliferation in numerous cells including breast cancer cells, however, the regulatory mechanism of KDM2B in cell proliferation of breast cancer cells, specifically in triple negative breast cancer (TNBC), remains largely unknown. In this study, we showed that higher expression level of KDM2B was associated with poor prognosis in TNBC. Using cell proliferation assay, we found that KDM2B promoted TNBC cell proliferation by suppressing the transcription of the cell cycle inhibitors p15INK4B, p16INK4A, and p57KIP2. Chromatin immunoprecipitation assay results showed that KDM2B bound to the promoters of these genes and thereby reduced the H3K4me3 and H3K36me2 levels, leading to the suppression of gene transcription in a histone demethylation activity-dependent manner. Silencing of p15INK4B, p16INK4A, and p57KIP2 in TNBC cells was shown to restore the promoting effect of KDM2B on TNBC cell proliferation. The present study reveals a novel cell regulatory mechanism through which KDM2B promotes TNBC cell proliferation by binding to the promoters of p15INK4B, p16INK4A, and p57KIP2, which reduces H3K4me3 and H3K36me2 levels to suppress gene transcription.

Suh S, Kim YH, Goh TS, et al.
mRNA Expression of SLC5A5 and SLC2A Family Genes in Papillary Thyroid Cancer: An Analysis of The Cancer Genome Atlas.
Yonsei Med J. 2018; 59(6):746-753 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The present study investigated the dynamics and prognostic role of messenger RNA (mRNA) expression responsible for ¹⁸F-fluorodeoxyglucose (FDG) uptake in FDG positron emission tomography (PET) and radioactive iodine (¹³¹I) uptake in whole-body radioactive iodine scans (WBS) in papillary thyroid cancer (PTC) patients.
MATERIALS AND METHODS: The primary and processed data were downloaded from the Genomic Data Commons Data Portal. Expression data for sodium/iodide symporter (solute carrier family 5 member 5, SLC5A5), hexokinase (HK1-3), glucose-6-phosphate dehydrogenase (G6PD), and glucose transporter (solute carrier family 2, SLC2A1-4) mRNA were collected.
RESULTS: Expression of SLC5A5 mRNA were negatively correlated with SLC2A1 mRNA and positively correlated with SLC2A4 mRNA. In PTC with BRAF mutations, expressions of SLC2A1, SLC2A3, HK2, and HK3 mRNA were higher than those in PTC without BRAF mutations. Expression of SLC5A5, SLC2A4, HK1, and G6PD mRNA was lower in PTC without BRAF mutation. PTCs with higher expression of SLC5A5 mRNA had more favorable disease-free survival, but no association with overall survival.
CONCLUSION: Expression of SLC5A5 mRNA was negatively correlated with SLC2A1 mRNA. This finding provides a molecular basis for the management of PTC with negative WBS using ¹⁸F-FDG PET scans. In addition, higher expression of SLC5A5 mRNA was associated with less PTC recurrence, but not with deaths.

Rahmani M, Talebi M, Hagh MF, et al.
Aberrant DNA methylation of key genes and Acute Lymphoblastic Leukemia.
Biomed Pharmacother. 2018; 97:1493-1500 [PubMed] Related Publications
DNA methylation is a dynamic process influencing gene expression by altering either coding or non-coding loci. Despite advances in treatment of Acute Lymphoblastic Leukemia (ALL); relapse occurs in approximately 20% of patients. Nowadays, epigenetic factors are considered as one of the most effective mechanisms in pathogenesis of malignancies. These factors are reversible elements which can be potentially regarded as therapy targets and disease prognosis. DNA methylation, which primarily serves as transcriptional suppressor, mostly occurs in CpG islands of the gene promoter regions. This was shown as a key epigenetic factor in inactivating various tumor suppressor genes during cancer initiation and progression. We aimed to review methylation status of key genes involved in hematopoietic malignancies such as IKZF1, CDKN2B, TET2, CYP1B1, SALL4, DLC1, DLX family, TP73, PTPN6, and CDKN1C; and their significance in pathogenesis of ALL. The DNA methylation alterations in promoter regions of the genes have been shown to play crucial roles in tumorigenesis. Methylation -based inactivation of these genes has also been reported as associated with prognosis in acute leukemia. In this review, we also addressed the association of gene expression and methylation pattern in ALL patients.

Ma Z, Peng P, Zhou J, et al.
Long Non-Coding RNA SH3PXD2A-AS1 Promotes Cell Progression Partly Through Epigenetic Silencing P57 and KLF2 in Colorectal Cancer.
Cell Physiol Biochem. 2018; 46(6):2197-2214 [PubMed] Related Publications
BACKGROUND/AIMS: Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide. Current evidence has revealed the key roles of long non-coding RNAs (IncRNAs) in multiple cancers, including CRC. In this study we identified the lncRNA SH3PXD2A-AS1 as a novel molecule associated with CRC progression by analyzing the publicly available data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets.
METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to examine the expression levels of SH3PXD2A-AS1 in CRC tissue samples and CRC cell lines. Cell viability examination, colony-formation experiments, ethynyl deoxyuridine (Edu) assays and flow cytometry were performed to investigate the roles of SH3PXD2A-AS1 in CRC proliferation, cell cycle regulation, and apoptosis. Transwell assays were used to explore the effects of SH3PXD2A-AS1 on CRC cells migration and invasion. A nude mice model was used to assess the effects of SH3PXD2A-AS1 on tumorigenesis in vivo. Subcellular fractionation, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (ChIP) assays were conducted to detect the molecular mechanisms of SH3PXD2A-ASl-mediated gene expression. Rescue assays were used to determine whether P57 and Kruppel-like factor 2 (KLF2) were involved in SH3PXD2A-ASl-dependent CRC proliferation.
RESULTS: We firstly found that SH3PXD2A-AS1 was significantly upregulated in CRC tissues and cell lines, and overexpression of SH3PXD2A-AS1 was correlated with tumor size, TNM stage, and lymph node metastasis in patients with CRC. Furthermore, SH3PXD2A-AS1 knockdown inhibited CRC cells proliferation, migration and invasion in vitro, and suppressed tumorigenesis in vivo. Mechanistic studies indicated that SH3PXD2A-AS1 could epiqenetically repress P57 and KLF2 expression through interaction with EZH2. Rescue experiments suggested that SH3PXD2A-ASl-mediated oncogenesis was impaired by overexpression of P57 or KLF2. Interestingly, the expression of SH3PXD2A-AS1 was inversely correlated with the expression of P57 and KLF2 in CRC tissue samples.
CONCLUSION: Our research presents the first evidence that SH3PXD2A-AS1 acts as an oncogene in CRC, and may be a promising diagnostic or therapeutic target in patients with CRC.

López-Nieva P, Fernández-Navarro P, Vaquero-Lorenzo C, et al.
RNA-Seq reveals the existence of a CDKN1C-E2F1-TP53 axis that is altered in human T-cell lymphoblastic lymphomas.
BMC Cancer. 2018; 18(1):430 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the impact of the deregulation of other genes such as CDKN1C, E2F1, and TP53 remains to be clarified. Interestingly, experiments in mouse models have proven that conditional T-cell specific deletion of Cdkn1c gene may induce a differentiation block at the DN3 to DN4 transition, and that the loss of this gene in the absence of Tp53 led to aggressive thymic lymphomas.
RESULTS: In this manuscript, we demonstrated that the simultaneous deregulation of CDKN1C, E2F1, and TP53 genes by epigenetic mechanisms and/or the deregulation of specific microRNAs, together with additional impairing of TP53 function by the expression of dominant-negative isoforms are common features in primary human T-LBLs.
CONCLUSIONS: Previous experimental work in mice revealed that T-cell specific deletion of Cdkn1c accelerates lymphomagenesis in the absence of Tp53. If, as expected, the consequences of the deregulation of the CDKN1C-E2F1-TP53 axis were the same as those experimentally demonstrated in mouse models, the disruption of this axis might be useful to predict tumor aggressiveness, and to provide the basis towards the development of potential therapeutic strategiesin human T-LBL.

Li X, Ruan X, Zhang P, et al.
TBX3 promotes proliferation of papillary thyroid carcinoma cells through facilitating PRC2-mediated p57
Oncogene. 2018; 37(21):2773-2792 [PubMed] Related Publications
The T-box transcription factor TBX3 has been implicated in the patterning and differentiation of a number of tissues during embryonic development, and is overexpressed in a variety of cancers; however, the precise function of TBX3 in papillary thyroid carcinoma (PTC) development remains to be determined. In the current study, we report downregulation of TBX3 in PTC cells delays the G1/S-phase transition, decreases cell growth in vitro, and inhibits tumor formation in vivo. We identified p57

Derlin T, Hartung D, Hueper K
18F-FDG PET/CT for Molecular Imaging of Hepatoblastoma in Beckwith-Wiedemann Syndrome.
Clin Nucl Med. 2018; 43(5):e164-e165 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth disorder variably characterized by macrosomia, macroglossia, congenital hypoglycemia, and hemihyperplasia. The BWS predisposes affected individuals to embryonal tumors during childhood. The BWS is caused by abnormal gene regulation in a particular region of chromosome 11. We present the case of a 1-year-old boy with BWS who underwent an F-FDG PET/CT scan for restaging of hepatoblastoma. On the F-FDG PET scan, increased tracer accumulation was observed in hepatoblastoma lesions. In addition, marked hemihyperplasia was noted. This case highlights the usefulness of F-FDG PET/CT for restaging of hepatoblastoma in BWS.

Qiu Z, Li Y, Zeng B, et al.
Downregulated CDKN1C/p57
Biochem Biophys Res Commun. 2018; 497(1):187-193 [PubMed] Related Publications
CDKN1C, also known as p57

Hölscher AS, Schulz WA, Pinkerneil M, et al.
Combined inhibition of BET proteins and class I HDACs synergistically induces apoptosis in urothelial carcinoma cell lines.
Clin Epigenetics. 2018; 10:1 [PubMed] Free Access to Full Article Related Publications
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types. We therefore investigated the effects of combined Romidepsin and JQ1 treatment on UC and benign urothelial control cells.
Results: JQ1 alone induced cell cycle arrest, but only limited apoptosis in eight UC cell lines with strongly varying IC
Conclusion: Our results demonstrate significant synergistic effects on induction of apoptosis in UC cells by the combination treatment with JQ1 and Romidepsin, but only minor effects in benign cells. Thus, this study established a promising new small-molecule combination therapy approach for UC.

Wang X, Lin Y, Peng L, et al.
MicroRNA-103 Promotes Proliferation and Inhibits Apoptosis in Spinal Osteosarcoma Cells by Targeting p57.
Oncol Res. 2018; 26(6):933-940 [PubMed] Related Publications
Osteosarcoma is one of the most aggressive malignancies with poor prognosis rates. Many studies have demonstrated that miRNAs were involved in osteosarcoma, but the role of miR-103a in osteosarcoma remains elusive. In this study, we detected the expression levels of miR-103 in osteosarcoma and non-osteosarcoma tissues and cell lines. The binding effect of miR-103 on p57 was detected by luciferase reporter assay. After altering expressions of miR-103 or p57, viability, migration, invasion, and apoptosis of MG63 cells and expressions of proteins related with the JNK/STAT and mTOR pathways were all detected. We found the higher expression of miR-103 in osteosarcoma tissues and cell lines compared with non-osteosarcoma tissues and cell lines. miR-103 overexpression promoted survival, migration, and invasion of MG63 cells. Knockdown of miR-103a inhibited cell survival, migration, and invasion by upregulating the expression of p57, which was a target of miR-103. Moreover, miR-103a overexpression activated the JNK/STAT and mTOR pathways probably through inhibiting p57 expression. In conclusion, miR-103a acted as an oncogene in osteosarcoma, probably through activating the JNK/STAT and mTOR pathways by inhibiting p57 expression.

Bylstra Y, Lysaght T, Thrivikraman J, et al.
Ethical frameworks for obtaining informed consent in tumour profiling: an evidence-based case for Singapore.
Hum Genomics. 2017; 11(1):31 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Genomic profiling of malignant tumours has assisted clinicians in providing targeted therapies for many serious cancer-related illnesses. Although the characterisation of somatic mutations is the primary aim of tumour profiling for treatment, germline mutations may also be detected given the heterogenous origin of mutations observed in tumours. Guidance documents address the return of germline findings that have health implications for patients and their genetic relations. However, the implications of discovering a potential but unconfirmed germline finding from tumour profiling are yet to be fully explored. Moreover, as tumour profiling is increasingly applied in oncology, robust ethical frameworks are required to encourage large-scale data sharing and data aggregation linking molecular data to clinical outcomes, to further understand the role of genetics in oncogenesis and to develop improved cancer therapies.
RESULTS: This paper reports on the results of empirical research that is broadly aimed at developing an ethical framework for obtaining informed consent to return results from tumour profiling tests and to share the biomolecular data sourced from tumour tissues of cancer patients. Specifically, qualitative data were gathered from 36 semi-structured interviews with cancer patients and oncology clinicians at a cancer treatment centre in Singapore. The interview data indicated that patients had a limited comprehension of cancer genetics and implications of tumour testing. Furthermore, oncology clinicians stated that they lacked the time to provide in depth explanations of the tumour profile tests. However, it was accepted from both patients and oncologist that the return potential germline variants and the sharing of de-identified tumour profiling data nationally and internationally should be discussed and provided as an option during the consent process.
CONCLUSIONS: Findings provide support for the return of tumour profiling results provided that they are accompanied with an adequate explanation from qualified personnel. They also support the use of broad consent regiments within an ethical framework that promotes trust and benefit sharing with stakeholders and provides accountability and transparency in the storage and sharing of biomolecular data for research.

Pinto EM, Rodriguez-Galindo C, Pounds SB, et al.
Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study.
J Clin Oncol. 2017; 35(35):3956-3963 [PubMed] Free Access to Full Article Related Publications
Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.

Lelic M, Fatusic Z, Iljazovic E, et al.
Challenges in the Routine Praxis Diagnosis of Hydatidiform Mole: a Tertiary Health Center Experience.
Med Arch. 2017; 71(4):256-260 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Hydatidiform moles (HM), presenting as complete (CHM) and partial (PHM) form, are rare pregnancy disorder. Diagnosis is based on clinical presentation, ultrasound imaging findings and pathological examination of products of conception. Protein p57, encoded by CKDN1C gene, is paternally imprinted and maternally expressed gene and provides quick insight in genetic basis of HM and allows distinction of CHM from all other conceptions. compare the preevacuational and pathohistological diagnosis with outcome of p57 immunostaining.
MATERIAL AND METHODS: All cases of HM diagnosed between January 2011 and December 2015 were included in this research. Maternal age, gestational age and input diagnosis data were recored. p57 immunostaining was performed in order to evaluate the diagnosis based on tissue slides examination.
RESULTS: There were 198 cases of histologically confirmed HM, 185 PHM, 12 CHM and one case of undefined HM. Mean maternal age in the CHM group was 24,7 and in the PHM group 26,9 years, with no significant differences among these two groups (p=0,27). For CHM mean gestational age was estimated at eight and for PHM 9,2 gestational weeks. Pregnant woman older than 40 years present significant earlier compared with younger woman (p<0,01), and those younger than 20 years tend to present at the beginning of the second trimester more often than older women (p<0,05). In the CHM group, 9 (75%) input diagnoses were mola in obs, and 3 (25%) of them were signed as abortion, unlike the PHM where 126 (67%) were qualified as abortion, 35 (19%) as blighted ovum, and 26 (14%) were suggestive for molar pregnancy. p57 immunostaining results confirmed all pathohistological diagnosis of CHM whereas 8% of PHM demonstrated divergent p57 expression.
CONCLUSION: PHM, compared with CHM, represent a greater diagnostic challenge for both gynecologist and pathologist even when presenting in more advanced pregnancies.

Ma Z, Gu S, Song M, et al.
Long non-coding RNA SNHG17 is an unfavourable prognostic factor and promotes cell proliferation by epigenetically silencing P57 in colorectal cancer.
Mol Biosyst. 2017; 13(11):2350-2361 [PubMed] Related Publications
Recently, substantial evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in multiple cancers including colorectal cancer (CRC). Utilizing publicly available lncRNA-expression-profiling data from the Gene Expression Omnibus (GEO) dataset GSE21510, we screened SNHG17 as a new candidate lncRNA associated with CRC development and progression. We further demonstrated that SNHG17 was upregulated in CRC tissues, and that its overexpression was significantly correlated with tumor size, TNM stage, and lymph node metastasis in CRC patients. Moreover, SNHG17 knockdown significantly inhibited the proliferation of CRC cells, and induced cell cycle G1/G0 phase arrest and cell apoptosis. Consistent with these findings, SNHG17 silencing inhibited tumor growth in vivo. Mechanistic studies revealed the capability of lncRNA SNHG17 to epigenetically suppress P57 by binding to enhancer of zeste homolog 2 (a key component of polycomb repressive complex 2) in CRC cells, and quantitative real-time polymerase chain reaction assays demonstrated that SNHG17 expression levels were inversely correlated with those of P57 in CRC tissues. Furthermore, rescue experiments confirmed that SNHG17 exerted oncogenic functions partly through regulating P57 expression. These findings represent the first reporting of the roles and mechanisms associated with SNHG17 in CRC progression, highlighting SNHG17 as a potential therapeutic target for CRC patients.

Rossi MN, Andresini O, Matteini F, Maione R
Transcriptional regulation of
Front Biosci (Landmark Ed). 2018; 23:83-108 [PubMed] Related Publications

Surti U, Yatsenko S, Hu J, et al.
Maternal GRB10 microdeletion is a novel cause of cystic placenta: Spectrum of genomic changes in the etiology of enlarged cystic placenta.
Placenta. 2017; 57:33-41 [PubMed] Related Publications
INTRODUCTION: The genetics and pathology of diploid complete and triploid partial hydatidiform moles have been well established. Enlarged cystic placenta often indicates an underlying etiology and is frequently associated with adverse pregnancy outcome. Several imprinted genes are strongly expressed in placental tissues and essential for normal placental growth and development. Disruption of these imprinted genes can lead to abnormal placental pathology and placental stunting or overgrowth. We present the genetic etiologies of five unusual mosaic cases of enlarged cystic placentas and report a novel etiology, mosaicism for deletion of the maternal GRB10 gene.
METHODS: Five mosaic placental mesenchymal dysplasia cases with discrete populations of "cystic" and "normal" villi and/or atypical p57
RESULTS: Genetic etiologies ranged from genome-wide changes, including mosaic androgenetic isodisomy and mosaic diandric triploidy, to a novel microdeletion of the maternally-expressed GRB10 gene. An abnormal mosaic population of cells was also detected in the fetus in two cases.
DISCUSSION: Four cases were mosaic for either diandric triploidy or an androgenetic cell population, and the enlarged cystic placentas were likely due to an excess of paternally-expressed growth promoting genes and also the absence of maternally-expressed growth restricting genes. Also we identified mosaicism for a novel microdeletion of the maternal GRB10 allele, a potent growth inhibitor, which resulted in placental overgrowth in the cystic area of one placenta. We advocate the use of ancillary techniques to investigate complex mosaic cases of enlarged cystic placentas to discover atypical genetic etiologies and to increase our understanding of the placental genome.

Ding L, Li R, Sun R, et al.
S-phase kinase-associated protein 2 promotes cell growth and motility in osteosarcoma cells.
Cell Cycle. 2017; 16(16):1547-1555 [PubMed] Free Access to Full Article Related Publications
Skp2 (S-phase kinase-associated protein 2) plays an oncogenic role in a variety of human cancers. However, the function of Skp2 in osteosarcoma (OS) is elusive. Therefore, in the current study, we explore whether Skp2 exerts its oncogenic function in OS. The cell growth, apoptosis, invasion and cell cycle were measured in OS cells after Skp2 overexpression. We found that overexpression of Skp2 enhanced cell growth, and inhibited cell apoptosis in OS cells. Moreover, we observed that upregulation of Skp2 accelerated cell cycle progression in OS cells. Furthermore, the ability of migration and invasion was enhanced in Skp2 overexpressing OS cells. Mechanically, our Western blotting data suggested that Skp2 decreased the expression of E-cadherin, Foxo1, p21, and p57, but increased MMP-9 in OS cells. In conclusion, our study demonstrated that Skp2 exhibited an oncogenic function in OS cells, suggesting that inhibition of Skp2 may be a novel approach for the treatment of OS.

Samadder A, Kar R
Utility of p57 immunohistochemistry in differentiating between complete mole, partial mole & non-molar or hydropic abortus.
Indian J Med Res. 2017; 145(1):133-137 [PubMed] Free Access to Full Article Related Publications
BACKGROUND & OBJECTIVES: There is considerable inter-observer variability in the diagnosis of molar pregnancies by histomorphological examination of products of conception (POC). The p57KIP2 gene is paternally imprinted and expressed from the maternal allele. On immunohistochemistry (IHC) with p57, complete mole (CM) shows absent staining whereas hydropic abortus (HA) and partial mole (PM) show positive staining. This study was undertaken to evaluate the role of p57 IHC along with histomorphology in differentiating between CM, PM and non-molar or HA.
METHODS: This was a cross-sectional study over a period of three and a half years on archival material. Detailed histomorphological review along with p57 IHC was carried out in 28 diagnosed cases (23 CM, 4 PM and 1 molar pregnancy not categorized) and 25 controls of four normal placentas and 21 POC (8 non-hydropic and 13 HA).
RESULTS: In 14.8 per cent (4/27) cases, there was discordance in accurate subtyping of molar pregnancy. One case of CM showed inconsistent IHC pattern. In 15.4 per cent (2/13) HA, molar pregnancy was final diagnosis. After final review, there were 25 CM, five PM, 22 non-molar controls including 10 HA and one not assigned (PM/HA). IHC with p57 was negative in 96 per cent CM and positive in 100 and 95 per cent PM and non-molar controls, respectively.
INTERPRETATION & CONCLUSIONS: This study showed that negative p57KIP2 immunostaining reliably identified CM and could be used in association with the histological findings to distinguish CM from its mimics.

Joseph NM, Pineda C, Rabban JT
DNA Genotyping of Nonmolar Donor Egg Pregnancies With Abnormal Villous Morphology: Allele Zygosity Patterns Prevent Misinterpretation as Complete Hydatidiform Mole.
Int J Gynecol Pathol. 2018; 37(2):191-197 [PubMed] Related Publications
DNA genotyping is the gold standard diagnostic test to distinguish hydatidiform moles from nonmolar but morphologically abnormal products of conception (POC). The test is based on comparison of alleles at 15 short tandem repeat loci in the chorionic villi of the POC to those in the maternal decidual tissue. If alleles in the POC are not present in the decidua, then the most concerning interpretation is that the POC has a paternal uniparental genome diagnostic of a complete hydatidiform mole (CHM). However, a nonmolar pregnancy from a donated egg would also appear the same because the maternal genome of the POC would match that of the maternal donor, not that of the decidua of the individual carrying the pregnancy. Not surprisingly, 2 cases of potential misclassification of the genotype of a donor egg POC as CHM have been reported in the literature. We hypothesize that the ratio of heterozygous loci to homozygous loci (so-called allele zygosity ratio) distinguishes the genotype of a donor egg POC from CHM. We compared the allele zygosity ratio in 11 nonmolar donor egg POC, 5 dispermic (heterozygous) CHM and 31 monospermic (homozygous) CHM, without knowledge of the use of a donor egg, the histologic findings, or results of p57 immunohistochemical staining. In all 47 cases, the alleles from the chorionic villi did not match those in the decidua. The average ratio of heterozygous to homozygous loci was 4:1 in donor egg POC and 1:3 in dispermic CHM (P<0.0001). Monospermic CHM contained 100% homozygous loci. p57 staining was intact in all donor egg POC. We conclude that the allele zygosity ratio is important to evaluate when interpreting the genotype of morphologically abnormal POC that does not match the genotype of the decidua. A high heterozygous:homozygous ratio should raise concern for a nonmolar donor egg pregnancy. Correlation of this variable along with review of the histologic findings and p57 immunohistochemistry may prevent misclassification of the genotype of a donor egg POC with abnormal villous morphology as a dispermic (heterozygous) CHM.

Roy AL
Pathophysiology of TFII-I: Old Guard Wearing New Hats.
Trends Mol Med. 2017; 23(6):501-511 [PubMed] Free Access to Full Article Related Publications
The biochemical properties of the signal-induced multifunctional transcription factor II-I (TFII-I) indicate that it is involved in a variety of gene regulatory processes. Although gene ablation in murine models and cell-based assays show that it is encoded by an essential gene, GTF2I/Gtf2i, its physiologic role in human disorders was relatively unknown until recently. Novel studies show that it is involved in an array of human diseases including neurocognitive disorders, systemic lupus erythematosus (SLE), and cancer. Here I bring together these diverse observations to illustrate its multiple pathophysiologic functions and further conjecture on how these could be related to its known biochemical properties. I expect that a better understanding of these 'structure-function' relationships would lead to future diagnostic and/or therapeutic potential.

Sun Y, Jin SD, Zhu Q, et al.
Long non-coding RNA LUCAT1 is associated with poor prognosis in human non-small lung cancer and regulates cell proliferation via epigenetically repressing p21 and p57 expression.
Oncotarget. 2017; 8(17):28297-28311 [PubMed] Free Access to Full Article Related Publications
Recently, long non-coding RNAs (lncRNAs) have been recognized as playing key roles in regulating cellular processes, such as proliferation, invasion, and metastasis. These lncRNAs have been shown to be abnormally expressed in tumorigenic processes. However, the role and clinical relevance of LUCAT1 in non-small-cell lung cancer (NSCLC) remain unclear. In this study, we found that the expression of LUCAT1 was significantly up-regulated in NSCLC tissues compared to non-tumor tissues, and its expression was associated with tumor size, tumor-node-metastasis (TNM) stage and overall survival (OS). Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo. Mechanistic investigations showed that LUCAT1 plays a key role in G0/G1 arrest. We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation. In summary, our results show that LUCAT1 could regulate tumorigenesis of NSCLC and be biomarker for poor prognosis in NSCLC.

Sun C, Ma P, Wang Y, et al.
KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression.
Dig Dis Sci. 2017; 62(6):1518-1526 [PubMed] Related Publications
BACKGROUND: Krüppel-like factors (KLFs) have been identified in multi-cancers and act as oncogenes or tumor suppressors. The function of KLF15, one member of KLFs, has not been well elucidated, especially in gastric cancer (GC).
AIMS: This study was designed to investigate the prognostic value and biological functions of KLF15 in GC.
METHODS: KLF15 protein expression in GC patients was evaluated by immunohistochemistry assays in 50 paired GC tissues and adjacent normal tissues, and correlations between KLF15 expression and clinicopathological characteristics and prognosis were analyzed. Then, we investigated the over-expression of KLF15 on cell proliferation and its mechanism in GC cells.
RESULTS: KLF15 expression levels were significantly down-regulated in GC tissues compared to adjacent normal tissues. And KLF15 expression was negatively correlated with clinical stage, lymphatic metastasis, and distant metastasis. Furthermore, KLF15 expression could predict prognosis in patients with GC. Moreover, over-expression of KLF15 could inhibit cell proliferation partly via regulating CDKN1A/p21 and CDKN1C/p57.
CONCLUSION: These findings demonstrate that KLF15 plays a significant role in GC progression and could be a therapeutic target for GC.

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