CDKN1B

Gene Summary

Gene:CDKN1B; cyclin dependent kinase inhibitor 1B
Aliases: KIP1, MEN4, CDKN4, MEN1B, P27KIP1
Location:12p13.1
Summary:This gene encodes a cyclin-dependent kinase inhibitor, which shares a limited similarity with CDK inhibitor CDKN1A/p21. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. Mutations in this gene are associated with multiple endocrine neoplasia type IV (MEN4). [provided by RefSeq, Apr 2014]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 1B
Source:NCBIAccessed: 10 March, 2017

Ontology:

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 (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: CDKN1B (cancer-related)

Lang T, Nie Y
MiR-148a participates in the growth of RPMI8226 multiple myeloma cells by regulating CDKN1B.
Biomed Pharmacother. 2016; 84:1967-1971 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to explore the influence of miR-148a on cell proliferation and cell cycle of multiple myeloma (MM) cell line RPMI8226 and the related molecular mechanism.
METHODS: The expression of miR-148a and CDKN1B in MM cells and primary cells of normal bone marrow were determined by RT-PCR and western blotting. The cell proliferation and cell cycle of miR-148a knockdown MM cells and normal MM cells were determined by flow cytometry. The protein expression of p-NPAT, p-Rb and p-CDC6 was determined in normal and miR-148a knockdown MM cells. Luciferase reported assay was used to explore the relationship between miR-148a and CDKN1B.
RESULTS: The level of miR-148a in MM cells was much higher than that in primary cells from healthy bone marrow samples, while the expression of CDKN1B was lower in MM cells. After knockdown of miR-148a, cell cycle mainly distributed at G0/G1 and the proliferation capacity of MM cells decreased. Knockdown of miR-148a significantly reduced protein expression of p-NPAT, p-Rb and p-CDC6. Luciferase reported assay showed that miR-148a could directly target CDKN1B at 3'-UTR.
CONCLUSIONS: High level of miR-148a inhibits CDK activity and promotes the proliferation of MM cells at least partly by downregulating CDKN1B.

Hayashi T, Kawano M, Ichimura T, et al.
Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma.
Anticancer Res. 2016; 36(10):4997-5007 [PubMed] Related Publications
Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Zhu W, Xue Y, Liang C, et al.
S100A16 promotes cell proliferation and metastasis via AKT and ERK cell signaling pathways in human prostate cancer.
Tumour Biol. 2016; 37(9):12241-12250 [PubMed] Related Publications
S100A16 is a member of the S100 calcium-binding protein family. It is overexpressed in many types of tumors and associated with proliferation, migration, and invasion; however, its function in human prostate cancer is unresolved. Our objective was to determine its effects and the underlying pathways of S100A16 in prostate cancer tissues and cells. We measured S100A16 expression by quantitative real-time polymerase and Western blotting in eight matched prostate cancer and adjacent normal tissues, and in three prostate cancer cell lines, DU-145, LNCaP, and PC-3, compared to a normal prostate epithelial cell line PrEC. DU-145 cells stably overexpressing S100A16 and PC-3 cells with S100A16 knockdown were established by transfection with S100A16 overexpression plasmid or shRNAs. Invasion, migration, and proliferation were analyzed by transwell assay, wound healing, and colony formation assays, respectively. Western blotting and invasion assays were performed to determine expressions and activation of AKT, ERK, p21, and p27. S100A16 was significantly overexpressed in both prostate cancer tissues and cells lines compared to normal controls (P < 0.05). Overexpression of S100A16 significantly promoted invasion, migration, and proliferation in prostate cancer cells in vitro, whereas silencing S100A16 showed the converse effects (P < 0.05). Furthermore, overexpression of S100A16 activated cell signaling proteins AKT and ERK and downregulated tumor suppressors p21 and p27. Specific inhibitors, LY294002 and PD98059, suppressed activation of AKT and ERK, which attenuated DU-145 cell clone formation and invasion induced by S100A16 overexpression. S100A16 may promote human prostate cancer progression via signaling pathways involving AKT, ERK, p21, and p27 downstream effectors. Our findings suggest that S100A16 may serve as a novel therapeutic or diagnostic target in human prostate cancer.

Abaza MS, Afzal M, Al-Attiyah RJ, Guleri R
Methylferulate from Tamarix aucheriana inhibits growth and enhances chemosensitivity of human colorectal cancer cells: possible mechanism of action.
BMC Complement Altern Med. 2016; 16(1):384 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Natural products are valuable sources for anticancer agents. In the present study, methylferulate (MF) was identified for the first time from Tamarix aucheriana. Spectral data were used for identification of MF. The potential of MF to control cell growth, cell cycle, apoptosis, generation of reactive oxygen species (ROS), cancer cell invasion, nuclear factor kappa B (NFkB) DNA-binding activity and proteasomal activities, as well as the enhancement of chemosensitivity in human colorectal cancer cells, were evaluated. The possible molecular mechanism of MF's therapeutic efficacy was also assessed.
METHODS: Column chromatography and spectral data were used for isolation and identification of MF. MTT, immunofluorescence, flow cytometry, in vitro invasion, fluoremetry, EIA and Real time qPCR were used to measure antiproliferative, chemo-sensitizing effects and other biochemical parameters.
RESULTS: MF showed a dose-dependent anti-proliferative effect on colorectal cancer cells (IC50 = 1.73 - 1.9 mM) with a nonsignificant cytotoxicity toward normal human fibroblast. Colony formation inhibition (P ≤ 0.001, 0.0001) confirmed the growth inhibition by MF. MF arrested cell cycle progression in the S and G2/M phases; induced apoptosis and ROS generation; and inhibited NF-kB DNA-binding activity, proteasomal activities and cell invasion in colorectal cancer cells. MF up-regulated cyclin-dependent kinase inhibitors (p19 (INK4D), p21(WAF1/CIP1), p27(KIP1)), pro-apoptotic gene expression (Bax, Bad, Apaf1, Bid, Bim, Smac) and caspases (caspase 2, 3, 6, 7, 8, 9). Moreover, MF down-regulated cyclin-dependent kinases (Cdk1, Cdk2) and anti-apoptotic gene expression (c-IAP-1, c-IAP-2, Bcl2,FLIP). In addition, MF differentially potentiated the sensitivity of colorectal cancer cells to standard chemotherapeutic drugs.
CONCLUSION: MF showed a multifaceted anti-proliferative and chemosensitizing effects. These results suggest the chemotherapeutic and co-adjuvant potential of MF.

Wang DD, Yang SJ, Chen X, et al.
miR-222 induces Adriamycin resistance in breast cancer through PTEN/Akt/p27(kip1) pathway.
Tumour Biol. 2016; 37(11):15315-15324 [PubMed] Related Publications
The high resistant rate of Adriamycin (Adr) is associated with a poor prognosis of breast cancer in women worldwide. Since miR-222 might contribute to chemoresistance in many cancer types, in this study, we aimed to investigate its efficacy in breast cancer through PTEN/Akt/p27 (kip1) pathway. Firstly, in vivo, we verified that miR-222 was upregulated in chemoresistant tissues after surgery compared with the paired preneoadjuvant samples of 21 breast cancer patients. Then, human breast cancer Adr-resistant cell line (MCF-7/Adr) was constructed to validate the pathway from the parental sensitive cell line (MCF-7/S). MCF-7/Adr and MCF-7/S were transfected with miR-222 mimics, miR-222 inhibitors, or their negative controls, respectively. The results showed that inhibition of miR-222 in MCF-7/Adr significantly increased the expressions of PTEN and p27 (kip1) and decreased phospho-Akt (p-Akt) both in mRNA and protein levels (p < 0.05) by using quantitative real-time PCR (qRT-PCR) and western blot. MTT and flow cytometry suggested that lower expressed miR-222 enhanced apoptosis and decreased the IC50 of MCF-7/Adr cells. Additionally, immunofluorescence demonstrated that the subcellular location of p27 (kip1) was dislocated resulting from the alteration of miR-222. Conversely, in MCF-7/S transfected with miR-222 mimics, upregulation of miR-222 is associated with decreasing PTEN and p27 (kip1) and increasing Akt accompanied by less apoptosis and higher IC50. Importantly, Adr resistance induced by miR-222 overexpression through PTEN/Akt/p27 was completely blocked by LY294002, an Akt inhibitor. Taken together, these data firstly elucidated that miR-222 could reduce the sensitivity of breast cancer cells to Adr through PTEN/Akt/p27 (kip1) signaling pathway, which provided a potential target to increase the sensitivity to Adr in breast cancer treatment and further improved the prognosis of breast cancer patients.

Cai F, Zhu Q, Miao Y, et al.
Desmoglein-2 is overexpressed in non-small cell lung cancer tissues and its knockdown suppresses NSCLC growth by regulation of p27 and CDK2.
J Cancer Res Clin Oncol. 2017; 143(1):59-69 [PubMed] Related Publications
PURPOSE: Desmoglein-2 (Dsg2) is a cell adhesion protein of the cadherin superfamily. Altered Dsg2 expression is associated with tumorigenesis. This study determined Dsg2 expression in non-small cell lung cancer (NSCLC) tissue specimens for association with clinicopathological and survival data and then assessed the effect of Dsg2 knockdown on regulation of NSCLC cell malignant behaviors in vitro and in nude mouse xenografts.
METHODS: qRT-PCR and Western blot were used to detect Dsg2 expression in 28 paired NSCLC and normal tissue samples. Immunohistochemistry was used to detect Dsg2 expression in 70 cases of paraffin-embedded NSCLC tissues. NSCLC A549, H1703, and H1299 cells were cultured with Dsg2 knockdown performed using Dsg2 siRNA. Cell viability, cell cycle, apoptosis, and colony formation were assessed. siRNA-transfected A549 cells were also used to generate tumor xenografts in nude mice.
RESULTS: Both Dsg2 mRNA and protein were highly expressed in NSCLC tissues and associated with NSCLC size, but not with overall survival of patients. Moreover, knockdown of Dsg2 expression reduced NSCLC cell proliferation and arrested them at the G1 phase of the cell cycle, but did not significantly affect NSCLC cell apoptosis. Dsg2 knockdown downregulated cyclin-dependent kinase 2 expression and upregulated p27 expression. Nude mouse xenograft assays showed that Dsg2 knockdown inhibited NSCLC xenograft growth in vivo.
CONCLUSION: This study revealed the importance of Dsg2 in suppression of NSCLC development and progression. Further studies will explore whether restoration of Dsg2 expression is a novel strategy in control of NSCLC.

Zatonski T, Ciesielska U, Nowinska K, et al.
Expression of Cell Cycle-Related Proteins p16, p27, p53 and Ki-67 in HPV-positive and -negative Samples of Papillomas of the Upper Respiratory Tract.
Anticancer Res. 2016; 36(8):3917-24 [PubMed] Related Publications
BACKGROUND: The role of human papillomavirus (HPV) infection as an etiological factor of respiratory tract papillomas has been described in numerous studies, however its role in malignant transformation has not been clearly defined. Depending on their oncogenic potential they have been classified as low- and high-risk HPVs. We analyzed the expression of four cell cycle-related proteins in order to understand the processes leading to malignant transformation.
MATERIALS AND METHODS: Fifty-six cases of pharyngeal and laryngeal papillomas were analyzed. Nested multiplex polymerase chain reactions to detect the presence of the HPV types, as well as immunohistochemical reactions were performed for the detection of cell cycle-related proteins p16, p27, p53 and Ki-67.
RESULTS: The presence of HPVs 6/11 and 16 was confirmed in 10/56 cases. The expression of all analyzed cell cycle-related proteins was increased in HPV-infected papillomas.
CONCLUSION: HPV infection of the upper respiratory tract may influence the expression of cell cycle-related proteins, that could indicate its possible role in the process of malignant transformation.

Patel AV, Chaney KE, Choi K, et al.
An ShRNA Screen Identifies MEIS1 as a Driver of Malignant Peripheral Nerve Sheath Tumors.
EBioMedicine. 2016; 9:110-9 [PubMed] Free Access to Full Article Related Publications
Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas that are a major source of mortality in neurofibromatosis type 1 (NF1) patients. To identify MPNST driver genes, we performed a lentiviral short hairpin (sh) RNA screen, targeting all 130 genes up-regulated in neurofibroma and MPNSTs versus normal human nerve Schwann cells. NF1 mutant cells show activation of RAS/MAPK signaling, so a counter-screen in RAS mutant carcinoma cells was performed to exclude common RAS-pathway driven genes. We identified 7 genes specific for survival of MPSNT cells, including MEIS1. MEIS1 was frequently amplified or hypomethylated in human MPSNTs, correlating with elevated MEIS1 gene expression. In MPNST cells and in a genetically engineered mouse model, MEIS1 expression in developing nerve glial cells was necessary for MPNST growth. Mechanistically, MEIS1 drives MPNST cell growth via the transcription factor ID1, thereby suppressing expression of the cell cycle inhibitor p27(Kip) and maintaining cell survival.

Halkova T, Dvorakova S, Sykorova V, et al.
Polymorphisms in selected DNA repair genes and cell cycle regulating genes involved in the risk of papillary thyroid carcinoma.
Cancer Biomark. 2016; 17(1):97-106 [PubMed] Related Publications
BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. In addition to causal somatic mutations in the BRAF gene and RET/PTC rearrangements, the contribution of single nucleotide polymorphisms (SNPs) in low-penetrance genes in the development of PTC has been proposed.
METHODS: Four SNPs in the XRCC1 (Arg399Gln, Arg280His, Arg194Trp and T-77C) and one SNP from each of three other genes participating in DNA repair pathways and/or cell cycle regulation (ATM Asp1853Asn, TP53 Arg72Pro, CDKN1B Val109Gly) were selected. The allelic and genotypic distributions of these variants as well as haplotypes of the XRCC1 were examined in 583 individuals comprising well-characterized cohorts of 209 PTC patients and 374 healthy volunteers. Correlations of polymorphism with clinical-pathological data and mutation status were performed.
RESULTS: XRCC1 T-77C polymorphism affects the genetic susceptibility for PTC development in men, the specific combination of XRCC1 haplotypes correlates with RET/PTC incidence, CDKN1B Val109Gly significantly influences the risk of developing PTC regardless of gender and in PTC cases, selected genotypes of TP53 Arg72Pro and ATM Asp1853Asn were significantly associated with monitored tumour characteristics.
CONCLUSION: It seems that SNPs in studied regulating genes contribute to the development of PTC and modify the tumour behaviour or characteristics.

Luo J, Chen Y, Li Q, et al.
CRM-1 knockdown inhibits extrahepatic cholangiocarcinoma tumor growth by blocking the nuclear export of p27Kip1.
Int J Mol Med. 2016; 38(2):381-90 [PubMed] Free Access to Full Article Related Publications
Cholangiocarcinoma is a deadly disease which responds poorly to surgery and conventional chemotherapy or radiotherapy. Early diagnosis is difficult due to the anatomical and biological characteristics of cholangiocarcinoma. Cyclin-dependent kinase inhibitor 1B (p27Kip1) is a cyclin‑dependent kinase inhibitor and in the present study, we found that p27Kip1 expression was suppressed in the nucleus and increased in the cytoplasm in 53 samples of cholangiocarcinoma from patients with highly malignant tumors (poorly-differentiated and tumor-node-metastsis (TNM) stage III-IV) compared with that in samples from 10 patients with chronic cholangitis. The expression of phosphorylated (p-)p27Kip1 (Ser10), one of the phosphorylated forms of p27Kip1, was increased in the patient samples with increasing malignancy and clinical stage. Coincidentally, chromosome region maintenance 1 (CRM-1; also referred to as exportin 1 or Xpo1), a critical protein responsible for protein translocation from the nucleus to the cytoplasm, was also overexpressed in the tumor samples which were poorly differentiated and of a higher clinical stage. Through specific short hairpin RNA (shRNA)-mediated knockdown of CRM-1 in the cholangiocarcinoma cell line QBC939, we identified an elevation of cytoplasmic p27Kip1 and a decrease of nuclear p27Kip1. Furthermore, the viability and colony formation ability of QBC939 cells was largely reduced with G1 arrest. Consistent with the findings of the in vitro experiments, in a xenograft mouse model, the tumors formed in the CRM-1 knockdown group were markedly smaller and weighed less than those in the control group in vivo. Taken together, these findings demonstrated that the interplay between CRM-1 and p27Kip1 may provide potentially potent biomarkers and functional targets for the development of future cholangiocarcinoma treatments.

Yang Y, Lu Y, Wang L, et al.
Skp2 is associated with paclitaxel resistance in prostate cancer cells.
Oncol Rep. 2016; 36(1):559-66 [PubMed] Related Publications
Prostate cancer is the most commonly diagnosed tumor in men in the United States. Patients with hormone-refractory prostate cancer are often treated with paclitaxel, but most of them eventually develop drug resistance. S-phase kinase associated protein 2 (Skp2) is a component of the SCF (Skp1-Cullin1-F-box) type of E3 ubiquitin ligase complexes. In the present study, we investigated the role of Skp2 in paclitaxel-resistant DU145-TxR or PC-3-TxR cells by Skp2 silencing or using Skp2 inhibitors. We first confirmed that Skp2 expression is up-regulated in DU145-TxR or PC-3-TxR cells compared with their parental cells DU145 or PC-3, respectively. Knockdown of Skp2 or Skp2 inhibitor treatment in DU145-TxR or PC-3-TxR cells restored paclitaxel sensitivity. E-cadherin was decreased while Vimentin was increased in PC-3-TxR or DU145-TxR cells. In addition, p27 expression was inversely correlated with Skp2 expression in DU145-TxR or PC-3-TxR cells. Moreover, p27 was found to increase in both Skp2 silencing PC-3-TxR and DU145-TxR cells. These results suggest that Skp2 is associated with prostate cancer cell resistance to paclitaxel. Skp2 may be a potential therapeutic target for drug-resistant prostate cancer.

Tonissi F, Lattanzio L, Astesana V, et al.
Reoxygenation Reverses Hypoxia-related Radioresistance in Head and Neck Cancer Cell Lines.
Anticancer Res. 2016; 36(5):2211-5 [PubMed] Related Publications
BACKGROUND/AIM: Head and neck cancer (HNC) is characterized by epidermal growth factor receptor (EGFR) overexpression and radiotherapy (RT) resistance. Cancer cells are able to survive and proliferate in hypoxic conditions. Hypoxia can be transiently interrupted by phases of reoxygenation. This work aimed to analyze the reoxygenation effect on proliferation in response to radiation in HNC cells.
MATERIALS AND METHODS: HNC cell lines CAL33 and CAL166 were subjected to an 8-Gy radiation dose in hypoxia and/or after reoxygenation. Cell proliferation and molecular factors involved in response to treatments were studied.
RESULTS: Cytotoxicity test confirmed radioresistance in hypoxia and highlighted that reoxygenation before RT restores sensitivity in both cell lines. Our results showed a similar proliferation inhibition effect and EGFR modulation but a different cell death mechanism in the two cell lines after treatment.
CONCLUSION: Reoxygenation before RT rescued radiosensitivity in HNC cells.

Kim CW, Go RE, Lee HM, et al.
Cigarette smoke extracts induced the colon cancer migration via regulating epithelial mesenchymal transition and metastatic genes in human colon cancer cells.
Environ Toxicol. 2017; 32(2):690-704 [PubMed] Related Publications
There was considerable evidence that exposure to cigarette smoke is associated with an increased risk for colon cancer. Nevertheless, the mechanism underlying the relationship between cigarette smoking and colon cancer remains unclear. Moreover, there were only a few studies on effects of complexing substance contained in cigarette smoke on colon cancer. Thus, we further investigated whether cigarette smoke extract (CSE) affects the cell cycle, apoptosis and migration of human metastatic colon cancer cells, SW-620. MTT assay revealed that SW-620 cell proliferation was significantly inhibited following treatments with all CSEs, 3R4F, and two-domestic cigarettes, for 9 days in a concentration-dependent manner. Moreover, CSE treatments decreased cyclin D1 and E1, and increased p21 and p27 proteins by Western blot analysis in SW-620 cells. Additionally, the treatment of the cells with CSE contributed to these effects expressing by apoptosis-related proteins. An increased migration or invasion ability of SW-620 cells following CSE treatment was also confirmed by a scratch or fibronectin invasion assay in vitro. In addition, the protein levels of E-cadherin as an epithelial maker were down-regulated, while the mesenchymal markers, N-cadherin, snail, and slug, were up-regulated in a time-dependent manner. A metastatic marker, cathepsin D, was also down-regulated by CSE treatment. Taken together, these results indicate that CSE exposure in colon cancer cells may deregulate the cell growth by altering the expression of cell cycle-related proteins and pro-apoptotic protein, and stimulate cell metastatic ability by altering epithelial-mesenchymal transition (EMT) markers and cathepsin D expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 690-704, 2017.

Panaccione A, Chang MT, Carbone BE, et al.
NOTCH1 and SOX10 are Essential for Proliferation and Radiation Resistance of Cancer Stem-Like Cells in Adenoid Cystic Carcinoma.
Clin Cancer Res. 2016; 22(8):2083-95 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
PURPOSE: Although the existence of cancer stem cells (CSC) in adenoid cystic carcinoma (ACC) has been proposed, lack of assays for their propagation and uncertainty about molecular markers prevented their characterization. Our objective was to isolate CSC from ACC and provide insight into signaling pathways that support their propagation.
EXPERIMENTAL DESIGN: To isolate CSC from ACC and characterize them, we used ROCK inhibitor-supplemented cell culture, immunomagnetic cell sorting, andin vitro/in vivoassays for CSC viability and tumorigenicity.
RESULTS: We identified in ACC CD133-positive CSC that expressed NOTCH1 and SOX10, formed spheroids, and initiated tumors in nude mice. CD133(+)ACC cells produced activated NOTCH1 (N1ICD) and generated CD133(-)cells that expressed JAG1 as well as neural differentiation factors NR2F1, NR2F2, and p27Kip1. Knockdowns ofNOTCH1, SOX10, and their common effectorFABP7had negative effects on each other, inhibited spheroidogenesis, and induced cell death pointing at their essential roles in CSC maintenance. Downstream effects ofFABP7knockdown included suppression of a broad spectrum of genes involved in proliferation, ribosome biogenesis, and metabolism. Among proliferation-linked NOTCH1/FABP7 targets, we identified SKP2 and its substrate p27Kip1. A γ-secretase inhibitor, DAPT, selectively depleted CD133(+)cells, suppressed N1ICD and SKP2, induced p27Kip1, inhibited ACC growthin vivo, and sensitized CD133(+)cells to radiation.
CONCLUSIONS: These results establish in the majority of ACC the presence of a previously uncharacterized population of CD133(+)cells with neural stem properties, which are driven by SOX10, NOTCH1, and FABP7. Sensitivity of these cells to Notch inhibition and their dependence on SKP2 offer new opportunities for targeted ACC therapies.

Fu HL, Shao L
Silencing of NUF2 inhibits proliferation of human osteosarcoma Saos-2 cells.
Eur Rev Med Pharmacol Sci. 2016; 20(6):1071-9 [PubMed] Related Publications
OBJECTIVE: NUF2 (NUF2, Ndc80 kinetochore complex component), which is essential for kinetochore-microtubule attachment in mitosis, has emerged as a critical mediator of the cell cycle in multiple tumour occurrences. In the present study, we aimed to investigate the role of NUF2 in osteosarcoma, one of the most common primary bone tumours in children and young adults.
MATERIALS AND METHODS: Lentivirus-mediated short-hairpin RNA (shRNA) targeting NUF2 (Lv-shNUF2) was employed for evaluation in human osteosarcoma Saos-2 cells. After NUF2 silencing, the proliferation of Saos-2 cells was significantly inhibited, as determined by the MTT assay.
RESULTS: The colony forming ability was also significantly decreased in Saos-2 cells infected with Lv-shNUF2. Flow cytometry revealed that downregulation of NUF2 in Saos-2 cells caused a remarkable accumulation of the cell population in the S phase. Furthermore, the expression levels of cell cycle regulators cyclin A and cyclin-dependent kinase 2 (CDK2) were notably decreased, whereas those of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, were increased in response to NUF2 knockdown in Saos-2 cells.
CONCLUSIONS: Our findings suggest that NUF2 might modulate cell proliferation via cell cycle control in Saos-2 cells. Downregulation of NUF2 by shRNA might be a novel strategy for early treatment of osteosarcoma using molecular-targeting therapy.

Kirouac DC, Du J, Lahdenranta J, et al.
HER2+ Cancer Cell Dependence on PI3K vs. MAPK Signaling Axes Is Determined by Expression of EGFR, ERBB3 and CDKN1B.
PLoS Comput Biol. 2016; 12(4):e1004827 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Understanding the molecular pathways by which oncogenes drive cancerous cell growth, and how dependence on such pathways varies between tumors could be highly valuable for the design of anti-cancer treatment strategies. In this work we study how dependence upon the canonical PI3K and MAPK cascades varies across HER2+ cancers, and define biomarkers predictive of pathway dependencies. A panel of 18 HER2+ (ERBB2-amplified) cell lines representing a variety of indications was used to characterize the functional and molecular diversity within this oncogene-defined cancer. PI3K and MAPK-pathway dependencies were quantified by measuring in vitro cell growth responses to combinations of AKT (MK2206) and MEK (GSK1120212; trametinib) inhibitors, in the presence and absence of the ERBB3 ligand heregulin (NRG1). A combination of three protein measurements comprising the receptors EGFR, ERBB3 (HER3), and the cyclin-dependent kinase inhibitor p27 (CDKN1B) was found to accurately predict dependence on PI3K/AKT vs. MAPK/ERK signaling axes. Notably, this multivariate classifier outperformed the more intuitive and clinically employed metrics, such as expression of phospho-AKT and phospho-ERK, and PI3K pathway mutations (PIK3CA, PTEN, and PIK3R1). In both cell lines and primary patient samples, we observed consistent expression patterns of these biomarkers varies by cancer indication, such that ERBB3 and CDKN1B expression are relatively high in breast tumors while EGFR expression is relatively high in other indications. The predictability of the three protein biomarkers for differentiating PI3K/AKT vs. MAPK dependence in HER2+ cancers was confirmed using external datasets (Project Achilles and GDSC), again out-performing clinically used genetic markers. Measurement of this minimal set of three protein biomarkers could thus inform treatment, and predict mechanisms of drug resistance in HER2+ cancers. More generally, our results show a single oncogenic transformation can have differing effects on cell signaling and growth, contingent upon the molecular and cellular context.

Hu JJ, Song W, Zhang SD, et al.
HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling.
Sci Rep. 2016; 6:23521 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
It is well accepted that HBx plays the major role in hepatocarcinogenesis associated with hepatitis B virus (HBV) infections. However, little was known about its role in regulating long noncoding RNAs (lncRNAs), a large group of transcripts regulating a variety of biological processes including carcinogenesis in mammalian cells. Here we report that HBx upregulates UCA1 genes and downregulates p27 genes in hepatic LO2 cells. Further studies show that the upregulated UCA1 promotes cell growth by facilitating G1/S transition through CDK2 in both hepatic and hepatoma cells. Knock down of UCA1 in HBx-expressing hepatic and hepatoma cells resulted in markedly increased apoptotic cells by elevating the cleaved caspase-3 and caspase-8. More importantly, UCA1 is found to be physically associated with enhancer of zeste homolog 2 (EZH2), which suppresses p27Kip1 through histone methylation (H3K27me3) on p27Kip1 promoter. We also show that knockdown of UCA1 in hepatoma cells inhibits tumorigenesis in nude mice. In a clinic study, UCA1 is found to be frequently up-regulated in HBx positive group tissues in comparison with the HBx negative group, and exhibits an inverse correlation between UCA1 and p27Kip1 levels. Our findings demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-UCA1/EZH2-p27Kip1 axis, and a potential target of HCC.

Yi X, Li Y, Zai H, et al.
KLF8 knockdown triggered growth inhibition and induced cell phase arrest in human pancreatic cancer cells.
Gene. 2016; 585(1):22-7 [PubMed] Related Publications
BACKGROUND: The transcription factor Krüppel-like factor 8 (KLF8) plays an important role in tumor development and growth, but its role in pancreatic cancer (PC) is not clear.
METHODS: KLF8 expression in human PC cell lines and tumor tissues was measured by quantitative real-time polymerase chain reaction and Western blot analyses. The effects of lentivirus mediated knockdown of KLF8 on proliferation and growth in Panc-1 pancreatic cancer cells were examined.
RESULTS: KLF8 was overexpressed in 5 pancreatic cancer cell lines and in samples from patients with PC. In Panc-1 cells, KLF8 knockdown inhibited cell proliferation, tumorigenicity, and induced G2/M phase arrest. KLF8 knockdown suppressed PC tumor growth in nude mice model. Western blot analysis showed that KLF8 knockdown in Panc-1 cells down-regulated the expression of CDK1/CDC2, cyclin B1, and cyclin D1 and up-regulated the expression of p21, and p27.
CONCLUSIONS: Overexpression of KLF8 may contribute to the progression of pancreatic cancer, and downregulation of KLF8 expression by lentivirus-delivered shRNA is a novel therapeutic approach for PC.

Fentiman IS
Male breast cancer is not congruent with the female disease.
Crit Rev Oncol Hematol. 2016; 101:119-24 [PubMed] Related Publications
It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC. Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females. MBC is almost always estrogen receptor positive (ER+ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs and an increase in risk of mortality compared to tamoxifen. The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. These important biological differences point the way to the development of new therapies for MBC based on differences rather than similarities with FBC.

Kim JH, Choi YK, Byun JK, et al.
Estrogen-related receptor γ is upregulated in liver cancer and its inhibition suppresses liver cancer cell proliferation via induction of p21 and p27.
Exp Mol Med. 2016; 48:e213 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
Orphan nuclear receptor estrogen-related receptor γ (ERRγ) regulates cell growth and tumorigenesis in various cancers. However, the clinical relevance of ERRγ to hepatocellular carcinoma (HCC) remains unclear. Here we examined the clinical significance of ERRγ in HCC and its potential as a therapeutic target. ERRγ levels in tissues from completely resected specimens from 190 HCC patients were examined immunohistochemically and their association with clinical stage and pathological grade was analyzed. Small interfering RNA (siRNA)-mediated knockdown of ERRγ (siRNA-ERRγ) or an ERRγ inverse agonist, GSK5182, were also used to examine the effects of ERRγ inhibition on the proliferation and growth of a human hepatoma cell line, PLC/PRF/5. Immunohistochemical analysis revealed that tumor tissues showed higher levels of ERRγ-positivity than adjacent non-tumor lesions. Tumors showing high levels of ERRγ immunoreactivity also had advanced tumor node metastasis (TNM) and Barcelona Clinic Liver Cancer stages and a higher Edmondson-Steiner grade. In addition, high-level expression of ERRγ in tumors of advanced TNM stage correlated with poorer overall survival. Treatment of PLC/PRF/5 cells with siRNA-ERRγ or GSK5182 inhibited proliferation through G1 arrest, increased expression of p21 and p27 and decreased expression of phosphorylated retinoblastoma protein. GSK5182-induced reactive oxygen species also suppressed the proliferation of PLC/PRF/5 cells. The present study showed that ERRγ expression is clinically significant in HCC; therefore, it can be considered a biomarker for HCC diagnosis. Moreover, the results provide a rationale for the use of ERRγ inhibitors such as GSK5182 as potential therapeutic agents.

Bolomsky A, Schlangen K, Schreiner W, et al.
Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment.
J Hematol Oncol. 2016; 9:17 [PubMed] Article available free on PMC after 15/04/2017 Related Publications
BACKGROUND: The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM.
METHODS: BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed.
RESULTS: We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209. Importantly, the anti-MM activity was upheld in the presence of stromal support or myeloma growth factors insulin-like growth factor 1 (IGF-1) and interleukin 6 (IL-6). In the MM microenvironment, PTC-209 impaired tube formation, impaired osteoclast development and decreased osteoblast formation in a dose-dependent manner (P < 0.01 at 1 μM, respectively). The latter might be attributed to an induction of DKK1 and was reversed by concurrent anti-DKK1 antibody treatment.
CONCLUSIONS: We confirmed overexpression of BMI-1 in MM highlighting its role as an attractive drug target and reveal therapeutic targeting of BMI-1 by PTC-209 as a promising novel therapeutic intervention for MM.

Liu Z, Yokoyama NN, Blair CA, et al.
High Sensitivity of an Ha-RAS Transgenic Model of Superficial Bladder Cancer to Metformin Is Associated with ∼240-Fold Higher Drug Concentration in Urine than Serum.
Mol Cancer Ther. 2016; 15(3):430-8 [PubMed] Free Access to Full Article Related Publications
While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplastic tissue. We investigated the basis of the unusual sensitivity of this model to metformin, and observed that following oral dosing, urothelium is exposed to drug concentrations via the urine that are approximately 240-fold higher than those in the circulation. In addition, we observed that bladder cancer cell lines (RT4, UMUC-3, and J82) with homozygous deletion of either TSC1 or PTEN are more sensitive to metformin than those (TEU2, TCCSUP, and HT1376) with wild-type TSC1 and PTEN genes. Our findings provide a strong rationale for clinical trials of oral metformin in treatment of superficial bladder cancer.

Tang YL, Huang LB, Lin WH, et al.
Butein inhibits cell proliferation and induces cell cycle arrest in acute lymphoblastic leukemia via FOXO3a/p27kip1 pathway.
Oncotarget. 2016; 7(14):18651-64 [PubMed] Free Access to Full Article Related Publications
Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.

McCampbell AS, Mittelstadt ML, Dere R, et al.
Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.
Curr Mol Med. 2016; 16(3):252-65 [PubMed] Related Publications
Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.

Zhang E, He X, Yin D, et al.
Increased expression of long noncoding RNA TUG1 predicts a poor prognosis of gastric cancer and regulates cell proliferation by epigenetically silencing of p57.
Cell Death Dis. 2016; 7:e2109 [PubMed] Free Access to Full Article Related Publications
Recent evidence highlights long noncoding RNAs (lncRNAs) as crucial regulators of cancer biology that contribute to tumorigenesis. LncRNA TUG1 was initially detected in a genomic screen for genes upregulated in response to taurine treatment in developing mouse retinal cells. Our previous study showed that TUG1 could affect cell proliferation through epigenetically regulating HOXB7 in human non-small cell lung cancer. However, the clinical significance and potential role of TUG1 in GC remains unclear. In this study, we found that TUG1 is significantly increased and is correlated with outcomes in gastric cancer (GC). Further experiments revealed that knockdown of TUG1 repressed GC proliferation both in vitro and in vivo. Mechanistic investigations showed that TUG1 has a key role in G0/G1 arrest. We further demonstrated that TUG1 was associated with PRC2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors, including p15, p16, p21, p27 and p57, thus contributing to the regulation of GC cell cycle and proliferation. Together, our results suggest that TUG1, as a regulator of proliferation, may serve as a candidate prognostic biomarker and target for new therapies in human GC.

Felicetti F, De Feo A, Coscia C, et al.
Exosome-mediated transfer of miR-222 is sufficient to increase tumor malignancy in melanoma.
J Transl Med. 2016; 14:56 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Growing evidence is showing that metastatic cell populations are able to transfer their characteristics to less malignant cells. Exosomes (EXOs) are membrane vesicles of endocytic origin able to convey their cargo of mRNAs, microRNAs (miRs), proteins and lipids from donors to proximal as well as distant acceptor cells. Our previous results indicated that miR-221&222 are key factors for melanoma development and dissemination. The aim of this study was to verify whether the tumorigenic properties associated with miR-222 overexpression can be also propagated by miR-222-containing EXOs.
METHODS: EXOs were isolated by UltraCentrifugation or Exoquick-TC(®) methods. Preparations of melanoma-derived vesicles were characterized by using the Nanosight™ technology and the expression of exosome markers analyzed by western blot. The expression levels of endogenous and exosomal miRNAs were examined by real time PCR. Confocal microscopy was used to evaluate transfer and uptake of microvesicles from donor to recipient cells. The functional significance of exosomal miR-222 was estimated by analyzing the vessel-like process formation, as well as cell cycle rates, invasive and chemotactic capabilities.
RESULTS: Besides microvesicle marker characterization, we evidenced that miR-222 exosomal expression mostly reflected its abundance in the cells of origin, correctly paralleled by repression of its target genes, such as p27Kip1, and induction of the PI3K/AKT pathway, thus confirming its functional implication in cancer. The possible differential significance of PI3K/AKT blockade was assessed by using the BKM120 inhibitor in miR-222-transduced cell lines. In addition, in vitro cultures showed that vesicles released by miR-222-overexpressing cells were able to transfer miR-222-dependent malignancy when taken-up by recipient primary melanomas. Results were confirmed by antagomiR-221&222 treatments and by functional observations after internalization of EXOs devoid of these miRs.
CONCLUSION: All together these data, besides generally confirming the role of miR-222 in melanoma tumorigenesis, supported its responsibility in the exosome-associated melanoma properties, thus further indicating this miR as potential diagnostic and prognostic biomarker and its abrogation as a future therapeutic option.

Wang D, Han S, Peng R, et al.
Depletion of histone demethylase KDM5B inhibits cell proliferation of hepatocellular carcinoma by regulation of cell cycle checkpoint proteins p15 and p27.
J Exp Clin Cancer Res. 2016; 35:37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: KDM5B is a jmjc domain-containing histone demethylase which remove tri-, di-, and monomethyl groups from histone H3 lysine 4 (H3K4). KDM5B has been determined as an oncogene in many malignancies. However, its expression and role in hepatocellular carcinoma (HCC) remain unknown.
METHODS: We detected the expression of KDM5B in HCC tissues and cell lines. Cell proliferation was performed to reveal the role of KDM5B depletion on HCC cells both in vivo and in vitro. Flow cytometry was used to analyze the cell cycle and chip analysis was conducted to determine the direct target of KDM5B.
RESULTS: KDM5B is frequently up-regulated in HCC specimens compared with adjacent normal tissues and its expression level was significantly correlated with tumor size, TNM stage, and Edmondson grade. Moreover, Kaplan-Meier survival analysis showed that patients with high levels of KDM5B expression had a relatively poor prognosis. Knockdown of KDM5B notably inhibits HCC cell proliferation both in vivo and in vitro via arresting the cell cycle at G1/S phase partly through up-regulation of p15 and p27. Further molecular mechanism study indicates that silencing of KDM5B promotes p15 and p27 expression by increasing histone H3K4 trimethylation in their promoters.
CONCLUSIONS: KDM5B could be a potentially therapeutic target, which provides a rationale for the development of histone demethylase inhibitors as a strategy against HCC.

Lima G, Santos E, Angelo H, et al.
Association between p21 Ser31Arg polymorphism and the development of cervical lesion in women infected with high risk HPV.
Tumour Biol. 2016; 37(8):10935-41 [PubMed] Related Publications
Infection by high-risk human papillomavirus (HR-HPV) and single nucleotide polymorphism (SNP) in genes involved in cell cycle control, as p21 and p27, are important factors in the development of different types of human cancers. This study aims at investigating whether both the p21 Ser31Arg and p27 V109G polymorphisms are associated with susceptibility to the development of cervical lesions in women HR-HPV positive. We analyzed 132 women HPV positive and with cervical lesions or CC and 154 healthy control (HPV negative and without cervical lesions). p21 Ser31Arg and p27 V109G polymorphisms were analyzed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and sequencing. The p21 31Arg allele was associated with susceptibility for the development of cervical lesions (P* = 0.0009), while p27 V109G polymorphism showed no significant differences for this association (P* = 0.89). However, the combined effect of the polymorphisms showed that the presence of the CC genotype (SNP p21 Ser31Arg) conferred protection for the development of cervical lesions (OR = 0.39). p21 Ser31Arg and p27 V109G polymorphisms were not associated with the grade of cervical lesions (CINI, CINII, and CINIII) or CC (P* > 0.05). The HR-HPV more frequent in this study were of 16 (57.6 %) and 18 (37.1 %) types; however, no association was observed when both polymorphisms and risk factors analyzed were compared (P* > 0.05). Our findings suggest a possible association between p21 Ser31tabArg polymorphism and susceptibility to the development of cervical lesions in women from Pernambuco. Brazil.

Wang Y, Xiao Y, Chen K, et al.
Enhancer of zeste homolog 2 depletion arrests the proliferation of hepatoblastoma cells.
Mol Med Rep. 2016; 13(3):2724-8 [PubMed] Related Publications
Hepatoblastoma is the most common type of malignant liver tumor in children. While outcomes have been greatly improved in the past decades, the treatment of advanced hepatoblastoma has remained challenging. Enhancer of zeste homologue 2 (EZH2), a member of the polycomb group regulators of gene activity, is amplified and overexpressed in a variety of cancers. However, the role of EZH2 in hepatoblastoma has remained to be fully elucidated. The purpose of the present study was to investigate the expression patterns of EZH2 in hepatoblastoma cells and to assess the anti‑cancer effects of EZH2 depletion. Western blot analysis revealed that EZH2 expression was significantly higher in hepatoblastoma specimens compared with that in peri‑tumor tissues, while p27 was reduced in hepatoblastoma. Suppression of EHZ2 using lentiviral small hairpin RNA inhibited hepatoblastoma cell proliferation, induced cell cycle arrest in G1 phase and enhanced the expression of G1/S‑phase checkpoint protein p27. These results suggested that EZH2 may represent a potential diagnostic marker and therapeutic target for the treatment of hepatoblastoma.

Xiea Y, Wangb R
Pttg1 Promotes Growth of Breast Cancer through P27 Nuclear Exclusion.
Cell Physiol Biochem. 2016; 38(1):393-400 [PubMed] Related Publications
BACKGROUND/AIMS: A role of Pituitary Tumor Transforming Gene 1 (Pttg1) in the carcinogenesis has been shown in some cancers, but not in BC (BC).
METHODS: We compared the levels of Pttg1 in the resected BC tissue with the adjacent normal breast tissue from the same patient. We modified Pttg1 levels in a BC cell line, MCF7, by either a Pttg1 transgene, or a Pttg1 shRNA. The cell growth was measured in an MTT assay. The cell apoptosis was measured by apoptosis assay. The nuclear protein of cell-cycle-related genes was examined in Pttg1-modifed BC cells. Co-immunoprecipitation was performed to examine the association of Pttg1 and p27.
RESULTS: We detected significantly higher levels of Pttg1 in the resected BC tissue, compared to the adjacent normal breast tissue from the same patient. Overexpression or depletion of Pttg1 in MCF7 significantly increased or inhibited cell growth, respectively. Changes in Pttg1 levels, however, did not alter cell apoptosis, suggesting that Pttg1 increases cell growth through augmented cell proliferation, rather than decreased cell apoptosis. Among all examined cell-cycle-related proteins in Pttg1-modifed BC cells, only nuclear p27 levels were significantly affected. Further, co-immunoprecipitation showed that Pttg1 directly associated with p27.
CONCLUSION: Pttg1 may increase BC cell growth through nuclear exclusion of p27, which highlights a novel molecular regulatory machinery in tumorigenesis of BC.

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