CDKN1B

Gene Summary

Gene:CDKN1B; cyclin-dependent kinase inhibitor 1B (p27, Kip1)
Aliases: KIP1, MEN4, CDKN4, MEN1B, P27KIP1
Location:12p13.1-p12
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:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinase inhibitor 1B
HPRD
Source:NCBIAccessed: 17 March, 2015

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 (1990-2015)
Graph generated 17 March 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 17 March, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: CDKN1B (cancer-related)

Zhao YF, Zhao JY, Yue H, et al.
FOXD1 promotes breast cancer proliferation and chemotherapeutic drug resistance by targeting p27.
Biochem Biophys Res Commun. 2015; 456(1):232-7 [PubMed] Related Publications
Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. As a member of the forkhead family, FOXD1 is required during kidney development and its inactivation results in failure of nephron progenitor cells. However, the role of FOXD1 in carcinogenesis and progression is still limited. Here, we reported that FOXD1 is a potential oncogene in breast cancer. We found that FOXD1 is up-regulated in breast cancer tissues. Depletion of FOXD1 expression decreases the ability of cell proliferation and chemoresistance in MDA-MB-231 cells, whereas overexpression of FOXD1 increases the ability of cell proliferation and chemoresistance in MCF-7 cells. Furthermore, we observed that FOXD1 induces G1 to S phase transition by targeting p27 expression. Our results suggest that FOXD1 may be a potential therapy target for patients with breast cancer.

Agarwal A, Mackenzie RJ, Besson A, et al.
BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein.
Blood. 2014; 124(22):3260-73 [PubMed] Article available free on PMC after 20/11/2015 Related Publications
Recent studies have revealed that p27, a nuclear cyclin-dependent kinase (Cdk) inhibitor and tumor suppressor, can acquire oncogenic activities upon mislocalization to the cytoplasm. To understand how these antagonistic activities influence oncogenesis, we dissected the nuclear and cytoplasmic functions of p27 in chronic myeloid leukemia (CML), a well-characterized malignancy caused by the BCR-ABL1 tyrosine kinase. p27 is predominantly cytoplasmic in CML and nuclear in normal cells. BCR-ABL1 regulates nuclear and cytoplasmic p27 abundance by kinase-dependent and -independent mechanisms, respectively. p27 knockdown in CML cell lines with predominantly cytoplasmic p27 induces apoptosis, consistent with a leukemogenic role of cytoplasmic p27. Accordingly, a p27 mutant (p27(CK-)) devoid of Cdk inhibitory nuclear functions enhances leukemogenesis in a murine CML model compared with complete absence of p27. In contrast, p27 mutations that enhance its stability (p27(T187A)) or nuclear retention (p27(S10A)) attenuate leukemogenesis over wild-type p27, validating the tumor-suppressor function of nuclear p27 in CML. We conclude that BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. These findings suggest that cytoplasmic mislocalization of p27 despite BCR-ABL1 inhibition by tyrosine kinase inhibitors may contribute to drug resistance, and effective therapeutic strategies to stabilize nuclear p27 must also prevent cytoplasmic mislocalization.

Anik A, Abaci A
Endocrine cancer syndromes: an update.
Minerva Pediatr. 2014; 66(6):533-47 [PubMed] Related Publications
Endocrine neoplasms comprise a variety of benign and malign tumors that arise from the endocrine glands or neuroendocrine tissues. Although most endocrine neoplasms are sporadic, others are secondary to mutations of many known tumor-predisposing genes. Endocrine cancer syndromes, including Multiple Endocrine Neoplasia type 1 (MEN1), Multiple Endocrine Neoplasia type 2 (MEN2A and MEN2B), Multiple Endocrine Neoplasia type 4 (MEN4) syndromes, and inherited syndromes with different endocrine neoplasms (von Hippel-Lindau disease, Carney complex, Neurofibromatosis type 1, others) are heterogeneous group of cancer susceptibility syndromes that affect one or more of the endocrine glands or neuroendocrine tissues. Genetic studies and researches as well as technological possibilities allowed for detection of new endocrine cancer syndromes and genes leading to tumor susceptibility. In addition, early detection of children at risk for endocrine cancer syndromes using molecular analysis methods provided opportunity to regular monitoring of potential malignancies and timely intervention for these cases (e.g. early prophylactic thyroidectomy in MEN2). This review will describe the clinical, genetic, diagnostic and therapeutic options for endocrine cancer syndromes based on the current literature data.

Yanagi T, Krajewska M, Matsuzawa S, Reed JC
PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.
Cancer Res. 2014; 74(20):5795-807 [PubMed] Article available free on PMC after 15/10/2015 Related Publications
PCTAIRE1 is distant relative of the cyclin-dependent kinase family that has been implicated in spermatogenesis and neuronal development, but it has not been studied in cancer. Here, we report that PCTAIRE1 is expressed in prostate, breast, and cervical cancer cells, where its RNAi-mediated silencing causes growth inhibition with aberrant mitosis due to defects in centrosome dynamics. PCTAIRE1 was not similarly involved in proliferation of nontransformed cells, including diploid human IMR-90 fibroblasts. Through yeast two-hybrid screening, we identified tumor suppressor p27 as a PCTAIRE1 interactor. In vitro kinase assays showed PCTAIRE1 phosphorylates p27 at Ser10. PCTAIRE1 silencing modulated Ser10 phosphorylation on p27 and led to its accumulation in cancer cells but not in nontransformed cells. In a mouse xenograft model of PPC1 prostate cancer, conditional silencing of PCTAIRE1 restored p27 protein expression and suppressed tumor growth. Mechanistic studies in HeLa cells showed that PCTAIRE1 phosphorylates p27 during the S and M phases of the cell cycle. Notably, p27 silencing was sufficient to rescue cells from mitotic arrest caused by PCTAIRE1 silencing. Clinically, PCTAIRE1 was highly expressed in primary breast and prostate tumors compared with adjacent normal epithelial tissues. Together our findings reveal an unexpected role for PCTAIRE1 in regulating p27 stability, mitosis, and tumor growth, suggesting PCTAIRE1 as a candidate cancer therapeutic target.

Hamidi H, Lu M, Chau K, et al.
KRAS mutational subtype and copy number predict in vitro response of human pancreatic cancer cell lines to MEK inhibition.
Br J Cancer. 2014; 111(9):1788-801 [PubMed] Related Publications
BACKGROUND: To study the molecular mechanism regulating sensitivity to MEK inhibition in pancreatic cancer cell lines.
METHODS: A growth inhibition assay determined sensitivity to MEK162 in a panel of 29 pancreatic cancer cell lines. For the same panel, KRAS mutational status and copy-number variation (CNV) was determine using PCR, array CGH and FISH. Two sensitive and two resistant cell lines were further interrogated for difference in baseline and MEK162-induced gene expression, as well as signal transduction using microarray and western blotting. Cell cycle and apoptosis analysis was measured by flow cytometry.
RESULTS: We report a strong correlation between both specific KRAS mutational subtype and CNV, and sensitivity to MEK inhibition. Cell lines with a KRAS (V12) mutation and KRAS gains or loss (n=7) are ∼10 times more resistant than those having neither a KRAS (V12) mutation nor KRAS CNV (n=14). Significant differences in baseline and MEK162-induced gene expression exist between the sensitive and resistant lines, especially in genes involved in RAS, EGF receptor and PI3K pathways. This was further supported by difference in signal transduction. MEK 162 blocked ERK1/2, as well as inhibited PI3K and S6 and increased p27KIP1 levels in the sensitive lines.
CONCLUSIONS: Given the potency of MEK162, it may be a promising new therapy for patients with pancreatic cancer and KRAS mutational subtypes, and CNV may serve as important biomarkers for selecting patients that benefit from MEK-targeting based on these preclinical data.

Atsaves V, Lekakis L, Drakos E, et al.
The oncogenic JUNB/CD30 axis contributes to cell cycle deregulation in ALK+ anaplastic large cell lymphoma.
Br J Haematol. 2014; 167(4):514-23 [PubMed] Related Publications
Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) frequently carries the t(2;5)(p23;q35) resulting in expression of NPM1(NPM)-ALK oncogenic kinase. The latter is capable of activating ERK kinase, which upregulates JUNB expression through ETS1. JUNB, in turn, interacts with the TNFRSF8 (CD30) gene promoter and induces CD30 (TNFRSF8) overexpression. However, the role of CD30 overexpression in ALK+ ALCL oncogenesis remains unknown. Here we show that the JUNB gene is frequently amplified in ALK+ ALCL, suggesting gene amplification as an additional underlying mechanism for JUNB overexpression. Silencing of JUNB resulted in reduced cell growth and colony formation associated with decreased activator protein-1 activity and G1/S and G2/M cell cycle arrest. These effects were linked to decreased CD30 levels, downregulation of CCNA2 (Cyclin A), CCND2 (Cyclin D2) and CCND3 (Cyclin D3) and upregulation of cyclin-dependent kinase inhibitors CDKN2A (p14) and CDKN1A (p21), but not CDKN1B (p27). Similar cell cycle changes were observed following the knock-down of TNFRSF8 gene or blockade of its function using anti-CD30 antibodies, which were associated with upregulation of CDKN2A and CDKN1A, but not CDKN1B. These findings indicate that JUNB may partly operate through CD30 signalling. Silencing of JUNB also sensitized NPM1-ALCL+ cells to standard chemotherapeutic agents. Our findings uncover the oncogenic role of the JUNB/CD30 axis and its potential as therapeutic target in ALK+ ALCL.

Hoellein A, Fallahi M, Schoeffmann S, et al.
Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma.
Blood. 2014; 124(13):2081-90 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.

Fang Y, Wang Y, Wang Y, et al.
A new tumour suppression mechanism by p27Kip1: EGFR down-regulation mediated by JNK/c-Jun pathway inhibition.
Biochem J. 2014; 463(3):383-92 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
p27Kip1 is a potent inhibitor of cyclin-dependent kinases that drive G1-to-S cell-cycle transition. Reduced p27Kip1 expression is prevalent in a wide range of human tumours; however, the exact mechanism(s) of p27Kip1-mediated tumour suppression remains obscure. In the present study, we identified a close inverse relationship between p27Kip1 and EGFR (epidermal growth factor receptor) expression: the parental T24 human bladder cancer cells had high p27Kip1 expression but low EGFR expression and, in striking contrast, the metastatic derivative of T24 (T24T) had low p27Kip1 expression but high EGFR expression. This relationship was also found in various human cancer tissues, and was not only just correlative but also causal; depletion of p27Kip1 in MEF (mouse embryonic fibroblast) cells resulted in markedly elevated EGFR expression, a result reproducible with an Egfr promoter-luciferase reporter in both T24 and MEF cells, suggesting transcriptional repression of EGFR by p27Kip1. Indeed, p27Kip1 was found to regulate EGFR expression via the JNK (c-Jun N-terminal kinase)/c-Jun transcription factor: p27Kip1 deficiency activated JNK/c-Jun, whereas inhibition of JNK/c-Jun by dominant-negative mutants dramatically repressed Egfr transcription. Furthermore, the proximal promoter of the Egfr gene was crucial for its transcription, where the recruiting activity of c-Jun was much greater in p27Kip1-/- cells than in p27Kip1+/+ cells. Introduction of GFP-p27Kip1 into T24T cells suppressed JNK/c-Jun activation, EGFR expression and anchorage-independent growth. The results of the present study demonstrate that p27Kip1 suppresses JNK/c-Jun activation and EGFR expression in MEFs and human bladder cancer cells, and the results obtained are consistent with those from human cancer specimens. The present study provides new insights into p27Kip1 suppression of cancer cell growth, migration and metastasis.

Zhang JP, Zhang H, Wang HB, et al.
Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma.
J Transl Med. 2014; 12:222 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: Transcription factor Sp1 is multifaceted, with the ability to function as an oncogene or a tumor suppressor, depending on the cellular context. We previously reported that Sp1 is required for the transcriptional activation of the key oncogenes in nasopharyngeal carcinoma (NPC), including B-lymphoma mouse Moloney leukemia virus insertion region 1 (Bmi1) and centromere protein H (CENPH), but the role of Sp1 and its underlying mechanisms in NPC remained largely unexplored. The objective of this study was to investigate the cellular function of Sp1 and to verify the clinical significance of Sp1 as a potential therapeutic target in NPC.
METHODS: The levels of Sp1 in the normal primary nasopharyngeal epithelial cells (NPECs) and NPC cell lines were analyzed by Quantitative Real-time RT-PCR (qRT-PCR) and Western blot. The location and expression of Sp1 in the NPC tissues were detected by immunohistochemistry staining (IHC). The effect of Sp1 knockdown on the cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype in NPC cells were evaluated by MTT, flow cytometry, clonogenicity analysis and sphere formation assay.
RESULTS: The mRNA and protein levels of Sp1 were elevated in NPC cell lines than in the normal primary NPECs. Higher expression of Sp1 was found in NPC tissues with advanced clinical stage (P=0.00036). Either inhibition of Sp1 activity by mithramycin A, the FDA-approved chemotherapeutic anticancer drug or Sp1 silencing by two distinct siRNA against Sp1 suppressed the growth of NPC cells. Mechanism analysis revealed that Sp1 silencing may suppress cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype through inducing the expression of p27 and p21, and impairing the expressions of the critical stem cell transcription factors (SCTFs), including Bmi1, c-Myc and KLF4 in NPC cells.
CONCLUSIONS: Sp1 was enriched in advanced NPC tissues and silencing of Sp1 significantly inhibited cell proliferation, clonogenicity, anchorage-independent growth and the stem-cell like phenotype of NPC cells, suggesting Sp1 may serve as an appealing drug target for NPC.

Cui YM, Jiang D, Zhang SH, et al.
FOXC2 promotes colorectal cancer proliferation through inhibition of FOXO3a and activation of MAPK and AKT signaling pathways.
Cancer Lett. 2014; 353(1):87-94 [PubMed] Related Publications
Abnormal expression of FOXC2 has been found in several human cancers. However, the role of FOXC2 in the progression of colorectal cancer (CRC) has not been well characterized. In analysis of 206 CRC specimens, we revealed that both high expression and nuclear localization of FOXC2 were correlated to aggressive characteristics and poor survival of patients with CRC. FOXC2 promoted cell proliferation through activation of MAPK and AKT pathways, subsequently down-regulating p27, up-regulating cyclin D1 and p-FOXO3a. Furthermore, FOXC2 nuclear localization was required for its promotion of cell proliferation. These findings suggest that FOXC2 plays an essential role in CRC progression and may serve as a valuable clinical prognostic marker of this disease.

Georgiadou D, Sergentanis TN, Sakellariou S, et al.
Cyclin D1, p16(INK) (4A) and p27(Kip1) in pancreatic adenocarcinoma: assessing prognostic implications through quantitative image analysis.
APMIS. 2014; 122(12):1230-9 [PubMed] Related Publications
The prognostic significance of cyclin D1, p16(INK) (4A) and p27(Kip1) expression has been documented in several human malignancies; however, their prognostic potential in pancreatic adenocarcinoma is still unclear. This study aimed to assess the correlation of the aforementioned molecules with clinicopathological parameters and prognosis. Sixty patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution; immunohistochemical staining of the studied markers was quantified by Ιmage analysis system. Cyclin D1 overexpression was positively associated with grade, neural infiltration and vascular invasion, whereas p27 positively correlated with age. Higher cyclin D1 expression indicated poorer survival (adjusted HR = 9.75, 95%CI: 1.48-64.31, p = 0.018, increment: one unit in H-score), whereas a marginal trend toward an association between p16 positivity and improved survival was observed (adjusted HR = 0.58, 95%CI: 0.32-1.05, p = 0.072 regarding positive vs negative cases). No significant association with overall survival was noted regarding p27. In conclusion, cyclin D1 overexpression and possibly p16 loss of expression in pancreatic adenocarcinoma seem to be adverse prognostic factors, whereas p27 expression did not seem to possess such prognostic properties. Further validation of the present findings in studies encompassing larger samples seems to be needed.

Zaharieva MM, Kirilov M, Chai M, et al.
Reduced expression of the retinoblastoma protein shows that the related signaling pathway is essential for mediating the antineoplastic activity of erufosine.
PLoS One. 2014; 9(7):e100950 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Erufosine is a new antineoplastic agent of the group of alkylphosphocholines, which interferes with signal transduction and induces apoptosis in various leukemic and tumor cell lines. The present study was designed to examine for the first time the mechanism of resistance to erufosine in malignant cells with permanently reduced expression of the retinoblastoma (Rb) protein. Bearing in mind the high number of malignancies with reduced level of this tumor-suppressor, this investigation was deemed important for using erufosine, alone or in combination, in patients with compromised RB1 gene expression. For this purpose, clones of the leukemic T-cell line SKW-3 were used, which had been engineered to constantly express differently low Rb levels. The alkylphosphocholine induced apoptosis, stimulated the expression of the cyclin dependent kinase inhibitor p27Kip1 and inhibited the synthesis of cyclin D3, thereby causing a G2 phase cell cycle arrest and death of cells with wild type Rb expression. In contrast, Rb-deficiency impeded the changes induced by erufosine in the expression of these proteins and abrogated the induction of G2 arrest, which was correlated with reduced antiproliferative and anticlonogenic activities of the compound. In conclusion, analysis of our results showed for the first time that the Rb signaling pathway is essential for mediating the antineoplastic activity of erufosine and its efficacy in patients with malignant diseases may be predicted by determining the Rb status.

Longuini VC, Lourenço DM, Sekiya T, et al.
Association between the p27 rs2066827 variant and tumor multiplicity in patients harboring MEN1 germline mutations.
Eur J Endocrinol. 2014; 171(3):335-42 [PubMed] Related Publications
OBJECTIVE: To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.
DESIGN: As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.
METHODS: Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.
RESULTS: There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.
CONCLUSIONS: Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.

Li Y, Liang C, Ma H, et al.
miR-221/222 promotes S-phase entry and cellular migration in control of basal-like breast cancer.
Molecules. 2014; 19(6):7122-37 [PubMed] Related Publications
The miR-221/222 cluster has been demonstrated to function as oncomiR in human cancers. miR-221/222 promotes epithelial-to-mesenchymal transition (EMT) and confers tamoxifen resistance in breast cancer. However, the effects and mechanisms by which miR-221/222 regulates breast cancer aggressiveness remain unclear. Here we detected a much higher expression of miR-221/222 in highly invasive basal-like breast cancer (BLBC) cells than that in non-invasive luminal cells. A microRNA dataset from breast cancer patients indicated an elevated expression of miR-221/222 in BLBC subtype. S-phase entry of the cell cycle was associated with the induction of miR-221/222 expression. miRNA inhibitors specially targeting miR-221 or miR-222 both significantly suppressed cellular migration, invasion and G1/S transition of the cell cycle in BLBC cell types. Proteomic analysis demonstrated the down-regulation of two tumor suppressor genes, suppressor of cytokine signaling 1 (SOCS1) and cyclin-dependent kinase inhibit 1B (CDKN1B), by miR-221/222. This is the first report to reveal miR-221/222 regulation of G1/S transition of the cell cycle. These findings demonstrate that miR-221/222 contribute to the aggressiveness in control of BLBC.

Wang X, Lin C, Zhao X, et al.
Acylglycerol kinase promotes cell proliferation and tumorigenicity in breast cancer via suppression of the FOXO1 transcription factor.
Mol Cancer. 2014; 13:106 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: Acylglycerol kinase (AGK) is reported to be overexpressed in multiple cancers. The clinical significance and biological role of AGK in breast cancer, however, remain to be established.
METHODS: AGK expression in breast cancer cell lines, paired patient tissues were determined using immunoblotting and Real-time PCR. 203 human breast cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the relationship between AGK expression and the clinicopathological features of breast cancer. Functional assays, such as colony formation, anchorage-independent growth and BrdU assay, and a xenograft tumor model were used to determine the oncogenic role of AGK in human breast cancer progression. The effect of AGK on FOXO1 transactivity was further investigated using the luciferase reporter assays, and by detection of the FOXO1 downstream genes.
RESULTS: Herein, we report that AGK was markedly overexpressed in breast cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of AGK significantly correlated with patients' clinicopathologic characteristics, including clinical stage and tumor-nodule-metastasis (TNM) classification. Breast cancer patients with higher levels of AGK expression had shorter overall survival compared to patients with lower AGK levels. We gained valuable insights into the mechanism of AGK expression in breast cancer cells by demonstrating that overexpressing AGK significantly enhanced, whereas silencing endogenous AGK inhibited, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. Furthermore, overexpression of AGK enhanced G1-S phase transition in breast cancer cells, which was associated with activation of AKT, suppression of FOXO1 transactivity, downregulation of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 and upregulation of the cell cycle regulator cyclin D1.
CONCLUSIONS: Taken together, these findings provide new evidence that AGK plays an important role in promoting proliferation and tumorigenesis in human breast cancer and may serve as a novel prognostic biomarker and therapeutic target in this disease.

Xu XD, Yang L, Zheng LY, et al.
Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses vasculogenic mimicry and proliferation of highly aggressive pancreatic cancer PaTu8988 cells.
BMC Cancer. 2014; 14:373 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: Pancreatic cancer is one of the most aggressive human malignancies with a extremely low 5-year survival rate. Hence, the search for more effective anti-pancreatic cancer agents is urgent.
METHODS: PaTu8988 pancreatic cancer cells were treated with different concentrations of suberoylanilide hydroxamic acid (SAHA), cell survival, proliferation, migration and vasculogenic mimicry (VM) were analyzed. Associated signaling changes were also analyzed by RT-PCR and Western blots.
RESULTS: Here, we reported that SAHA, a histone deacetylase inhibitor (HDACi), exerted significant inhibitory efficiency against pancreatic cancer cell survival, proliferation, migration and VM. SAHA dose-dependently inhibited PaTu8988 pancreatic cancer cell growth with the IC-50 of 3.4 ± 0. 7 μM. Meanwhile, SAHA suppressed PaTu8988 cell cycle progression through inducing G2/M arrest, which was associated with cyclin-dependent kinase 1 (CDK-1)/cyclin-B1 degradation and p21/p27 upregulation. Further, SAHA induced both apoptotic and non-apoptotic death of PaTu8988 cells. Significantly, SAHA suppressed PaTu8988 cell in vitro migration and cell-dominant tube formation or VM, which was accompanied by semaphorin-4D (Sema-4D) and integrin-β5 down-regulation. Our evidences showed that Akt activation might be important for Sema-4D expression in PaTu8988 cells, and SAHA-induced Sema-4D down-regulation might be associated with Akt inhibition.
CONCLUSIONS: This study is among the first to report the VM formation in cultured human pancreatic cancer cells. And we provided strong evidence to suggest that SAHA executes significant anti-VM efficiency in the progressive pancreatic cancer cells. Thus, SAHA could be further investigated as a promising anti-pancreatic cancer agent.

Zhang L, Dong Y, Zhu N, et al.
microRNA-139-5p exerts tumor suppressor function by targeting NOTCH1 in colorectal cancer.
Mol Cancer. 2014; 13:124 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: miR-139-5p was identified to be significantly down-regulated in colon tumor tissues by miRNA array. We aimed to clarify its biological function, molecular mechanisms and direct target gene in colorectal cancer (CRC).
METHODS: The biological function of miR-139-5p was examined by cell growth, cell cycle and apoptosis analysis in vitro and in vivo. miR-139-5p target gene and signaling pathway was identified by luciferase activity assay and western blot.
RESULTS: miR-139-5p was significantly down-regulated in primary tumor tissues (P < 0.0001). Ectopic expression of miR-139-5p in colon cancer cell lines significantly suppressed cell growth as evidenced by cell viability assay (P < 0.001) and colony formation assay (P < 0.01) and in xenograft tumor growth in nude mice (P < 0.01). miR-139-5p induced apoptosis (P < 0.01), concomitantly with up-regulation of key apoptosis genes including cleaved caspase-8, caspase-3, caspase-7 and PARP. miR-139-5p also caused cell cycle arrest in G0/G1 phase (P < 0.01), with upregulation of key G0/G1 phase regulators p21Cip1/Waf1 and p27Kip1. Moreover, miR-139-5p inhibited cellular migration (P < 0.001) and invasiveness (P < 0.001) through the inhibition of matrix metalloproteinases (MMP)7 and MMP9. Oncogene NOTCH1 was revealed to be a putative target of miR-139-5p, which was inversely correlated with miR-139-5p expression (r = -0.3862, P = 0.0002).
CONCLUSIONS: miR-139-5p plays a pivotal role in colon cancer through inhibiting cell proliferation, metastasis, and promoting apoptosis and cell cycle arrest by targeting oncogenic NOTCH1.

Mitsumori T, Nozaki Y, Kawashima I, et al.
Hypoxia inhibits JAK2V617F activation via suppression of SHP-2 function in myeloproliferative neoplasm cells.
Exp Hematol. 2014; 42(9):783-92.e1 [PubMed] Related Publications
The hypoxic microenvironment of the bone marrow, known as the hypoxic niche, supports hematopoietic stem cell quiescence and maintains long-term repopulation activity. Hypoxia also affects the expansion of progenitor cells and enhances erythropoiesis and megakaryopoiesis. In contrast to the known effects of hypoxia on normal hematopoiesis, the effects of the hypoxic environment of the bone marrow on the pathogenesis of myeloproliferative neoplasms (MPNs) have not been well studied. In the present study, we investigated the role of the hypoxic environment in the pathophysiology of MPNs, focusing on JAK2V617F, a major driver of mutation in Philadelphia-negative MPNs. We found that the activity of JAK2V617F was suppressed in hypoxic conditions not only in JAK2V617F-positive leukemia cells, but also in primary peripheral blood mononuclear cells from patients with polycythemia vera. Concomitant with the inhibition of JAK2V617F activity, hypoxia increased the expression of p27/KIP1, the primary negative regulator of the cell cycle, and inhibited cell cycle progression in JAK2V617F-positive leukemia cell lines. The spontaneous erythroid colony formation of primary cells from polycythemia vera patients was also suppressed under hypoxic conditions. We also revealed that the hypoxia-induced overproduction of reactive oxygen species played a crucial role in the inhibition of JAK2V617F through the oxidation and inhibition of SHP-2, a protein tyrosine phosphatase that contains SH-2, which is required for JAK2 activation. In conclusion, a hypoxic environment may modulate JAK2-positive MPN cell fate and disease progression through the suppression of SHP-2 function and the subsequent suppression of JAK2V617F activity.

Wang XH, Cai P, Wang MH, Wang Z
microRNA‑25 promotes osteosarcoma cell proliferation by targeting the cell‑cycle inhibitor p27.
Mol Med Rep. 2014; 10(2):855-9 [PubMed] Related Publications
An increasing body of evidence indicates that microRNAs (miRNAs), a class of small non‑coding RNAs, are often aberrantly expressed in human osteosarcoma. This study aimed to investigate the effects of miR‑25 and to identify its potential target genes in osteosarcoma (OS) cells. First, the expression of miR‑25 was detected by reverse transcription‑quantitative polymerase chain reaction (RT-qPCR), which revealed a significant upregulation of miR‑25 in osteosarcoma tissues compared to the adjacent healthy tissues. To investigate the role of miR‑25 in osteosarcoma cell proliferation, the miR‑25 precursor was next transfected into Saos‑2 and U2OS cells. Overexpression of miR‑25 promoted cell proliferation in vitro and tumor growth in a xenograft mouse model. In addition, our results revealed that the protein expression of p27, a cell‑cycle inhibitor, is negatively regulated by miR‑25. Restoring the p27 level in miR‑25‑overexpressing cells reversed the enhancing effect of miR‑25 on cell proliferation. Therefore, miR‑25 may act as an onco‑miRNA in osteosarcoma, which provides new perspectives in cancer treatment strategies based on molecular targeting.

Xu H, Choe C, Shin SH, et al.
Silencing of KIF14 interferes with cell cycle progression and cytokinesis by blocking the p27(Kip1) ubiquitination pathway in hepatocellular carcinoma.
Exp Mol Med. 2014; 46:e97 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Although it has been suggested that kinesin family member 14 (KIF14) has oncogenic potential in various cancers, including hepatocellular carcinoma (HCC), the molecular mechanism of this potential remains unknown. We aimed to elucidate the role of KIF14 in hepatocarcinogenesis by knocking down KIF14 in HCC cells that overexpressed KIF14. After KIF14 knockdown, changes in tumor cell growth, cell cycle and cytokinesis were examined. We also examined cell cycle regulatory molecules and upstream Skp1/Cul1/F-box (SCF) complex molecules. Knockdown of KIF14 resulted in suppression of cell proliferation and failure of cytokinesis, whereas KIF14 overexpression increased cell proliferation. In KIF14-silenced cells, the levels of cyclins E1, D1 and B1 were profoundly decreased compared with control cells. Of the cyclin-dependent kinase inhibitors, the p27(Kip1) protein level specifically increased after KIF14 knockdown. The increase in p27(Kip1) was not due to elevation of its mRNA level, but was due to inhibition of the proteasome-dependent degradation pathway. To explore the pathway upstream of this event, we measured the levels of SCF complex molecules, including Skp1, Skp2, Cul1, Roc1 and Cks1. The levels of Skp2 and its cofactor Cks1 decreased in the KIF14 knockdown cells where p27(Kip1) accumulated. Overexpression of Skp2 in the KIF14 knockdown cells attenuated the failure of cytokinesis. On the basis of these results, we postulate that KIF14 knockdown downregulates the expression of Skp2 and Cks1, which target p27(Kip1) for degradation by the 26S proteasome, leading to accumulation of p27(Kip1). The downregulation of Skp2 and Cks1 also resulted in cytokinesis failure, which may inhibit tumor growth. To the best of our knowledge, this is the first report that has identified the molecular target and oncogenic effect of KIF14 in HCC.

Wang S, Jiang Y, Liu J, et al.
Revisiting the role of MCL1 in tumorigenesis of solid cancer: gene expression correlates with antiproliferative phenotype in breast cancer cells and its functional regulatory variants are associated with reduced cancer susceptibility.
Tumour Biol. 2014; 35(8):8289-99 [PubMed] Related Publications
Compared to the well-defined anti-apoptotic role of myeloid cell leukemia sequence 1 (MCL1), its antiproliferative function in tumorigenesis is less studied. We had recently reported that regulatory variants of MCL1 contribute to enhanced promoter activity but reduced risk of lung cancer. We hypothesized that MCL1 expression may manifest antiproliferative phenotype and its functional variations may have etiological relevance for breast cancer. We manipulated MCL1 expression in MCF-7 cells and MDA231 with overexpression and knockdown, analyzed the effects on cell viability and cell cycling phase, and characterized the correlation with expression profiles of key regulators of cell cycle. We further genotyped the -190 insertion polymorphism and the neighboring single nucleotide polymorphisms (SNPs) in 745 breast cancer patients and 537 controls and analyzed their association with cancer risk. We confirmed that heightened expression of MCL1 resulted in decreased proliferation ability of breast cancer cells. We further observed that MCL1 overexpression in breast cancer cells resulted in cell cycle progression arresting in S phase and concomitant enhanced expression of p27, which could be rescued by p27 knockdown with co-transfection of small interfering RNA (siRNA). Furthermore, we found a significant reduction in breast cancer risk [odds ratio (OR) = 0.74; 95 % confidence interval (CI) = 0.59-0.93] associated with -190 insertion genotype; the expression-enhancing regulatory haplotype (OR 0.79; 95 % CI 0.66-0.95) and diplotype (OR 0.71; 95 % CI 0.57-0.89) were consistently associated with decreased cancer susceptibility. The study demonstrates that the expression-enhancing regulatory variants of MCL1 are protective modifiers of breast cancer risk, and reduced cell proliferation and arrested cell cycle progression partly mediated by p27 might be the underlying mechanism.

Tonelli F, Giudici F, Giusti F, et al.
A heterozygous frameshift mutation in exon 1 of CDKN1B gene in a patient affected by MEN4 syndrome.
Eur J Endocrinol. 2014; 171(2):K7-K17 [PubMed] Related Publications
OBJECTIVE: Multiple endocrine neoplasia type 4 (MEN4) is an autosomal dominant disorder that presents with a spectrum of clinical manifestations overlapping with those of MEN1 syndrome. It is caused by inactivating mutations of the CDKN1B gene, encoding for p27(kip1) cyclin-dependent kinase 2 inhibitor, implicated in cell cycle control. Eight mutations of CDKN1B in MEN4 patients have been published so far. The aim of this study was to characterize the molecular basis of a case of MEN1-like syndrome with a neuroendocrine tumor and persistent primary hyperparathyroidism (PHPT).
METHODS: Clinical, biochemical, and genetic evaluation were undertaken in the proband (a 53-year-old Caucasian woman) and in one 34-year-old son. The proband was operated for recurrent PHPT. Sequence analysis of the MEN1 and CDKN1B genes was performed on constitutional and parathyroid tissue DNA. Staining for p27 was carried out in parathyroid tissue.
RESULTS: Neither MEN1 mutations nor large deletions encompassing the MEN1 gene on chromosome 11q13.1 could be detected in the proband. A germline frameshift mutation of CDKN1B (371delCT) was revealed, predicted to generate a truncated p27 (CDKN1B) protein. This mutation was confirmed on somatic DNA from the pathological parathyroid tissue, with the retention of the WT allele.
CONCLUSIONS: We report a germline heterozygote frameshift mutation of the CDKN1B gene in a Caucasian woman with a long clinical history of MEN1-like multiple endocrine tumors, along with the finding of the mutation in her son. This is the first report of positive CDKN1B mutation analysis in a male subject and also the first description of recurrent hyperparathyroidism in MEN4.

Kwon S, Choi KC, Kim YE, et al.
Monoclonal antibody targeting of the cell surface molecule TM4SF5 inhibits the growth of hepatocellular carcinoma.
Cancer Res. 2014; 74(14):3844-56 [PubMed] Related Publications
The cell surface transmembrane receptor TM4SF5 has been implicated in hepatocellular carcinoma (HCC), but its candidacy as a therapeutic target has not been evaluated. Building on findings that immunization with a peptide vaccine targeting human TM4SF5 can exert prophylactic and therapeutic effects in a murine model of HCC, we developed a monoclonal antibody to characterize expression of TM4SF5 in HCC and to target its function there as an anticancer strategy. We found that the antibody modulated cell signaling in HCC cells in vitro, reducing cell motility, modulating E-cadherin expression, altering p27(kip1) localization, and increasing RhoA activity. Using a mouse xenograft model of human HCC, we documented the in vivo efficacy of the antibody, which suppressed tumor growth in either tumor prevention or treatment designs. Our work offers a preclinical proof of concept for TM4SF5 as a promising target for antibody therapeutics to treat HCC. Cancer Res; 74(14); 3844-56. ©2014 AACR.

Watanabe A, Suzuki H, Yokobori T, et al.
Stathmin1 regulates p27 expression, proliferation and drug resistance, resulting in poor clinical prognosis in cholangiocarcinoma.
Cancer Sci. 2014; 105(6):690-6 [PubMed] Related Publications
Patients with extrahepatic cholangiocarcinoma (EHCC) have a poor prognosis; postoperative survival depends on cancer progression and therapeutic resistance. The mechanism of EHCC progression needs to be clarified to identify ways to improve disease prognosis. Stathmin1 (STMN1) is a major cytosolic phosphoprotein that regulates microtubule dynamics and is associated with malignant phenotypes and chemoresistance in various cancers. Recently, STMN1 was reported to interact with p27, an inhibitor of cyclin-dependent kinase complexes. Eighty EHCC cases were studied using immunohistochemistry and clinical pathology to determine the correlation between STMN1 and p27 expression; RNA interference to analyze the function of STMN1 in an EHCC cell line was also used. Cytoplasmic STMN1 expression correlated with venous invasion (P = 0.0021) and nuclear p27 underexpression (P = 0.0011). Patients in the high-STMN1-expression group were associated with shorter recurrence-free survival and overall survival than those in the low-expression group. An in vitro protein-binding assay revealed that cytoplasmic STMN1 bound to p27 in the cytoplasm, but not in the nucleus of EHCC cells. Moreover, p27 accumulated in EHCC cells after STMN1 suppression. STMN1 knockdown inhibited proliferation and increased the sensitivity of EHCC cells to paclitaxel. STMN1 contributes to a poor prognosis and cancer progression in EHCC patients. Understanding the regulation of p27 by STMN1 could provide new insights for overcoming therapeutic resistance in EHCC.

Aoki T, Motoi F, Sakata N, et al.
Somatostatin analog inhibits the growth of insulinoma cells by p27-mediated G1 cell cycle arrest.
Pancreas. 2014; 43(5):720-9 [PubMed] Related Publications
OBJECTIVES: Although the somatostatin analog octreotide (OCT) has been used for uncontrollable insulinoma, the mechanism involved is still unknown. The aim of this study was to elucidate the therapeutic effect of OCT for insulinoma.
METHODS: Mouse insulinoma cell line MIN6 cells were cultured with OCT to clarify its antiproliferative effects, the expression of somatostatin receptor subtypes, cell cycle, p27 expression, and cdc2 kinase activity. The changes of the messenger RNA expression profiles were examined by microarray analysis. Intraperitoneal OCT treatment was given to insulinoma model IT6 mice for 4 weeks.
RESULTS: MIN6 cells expressed somatostatin receptor 2A, 3, and 5 under the OCT treatment. Octreotide showed a dose-dependent antiproliferative effect on MIN6 cells but not on the other cell lines. p27 expression and cdc2 kinase activity in MIN6 cells became prominent with OCT treatment. At the messenger RNA level, several molecules in the mitogen-activated protein kinase signaling pathway were downregulated. The sizes of the individual tumors tended to be smaller in the OCT-treated group. p27 expression was seen in the tumor tissue, but no apoptotic marker was detected.
CONCLUSION: Octreotide acted through a cytostatic mechanism and could be an effective therapy for insulinoma.

Shi Y, Wang E
Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic review.
Arch Pathol Lab Med. 2014; 138(4):564-9 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.

Zuo X, Qin Y, Zhang X, et al.
Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI.
Oncol Rep. 2014; 31(5):2358-64 [PubMed] Related Publications
ARHI is a maternally imprinted tumor suppressor gene that is expressed in normal breast epithelial cells but not in most breast cancer cells. Aberrant methylation and hypernomic histone deacetylation have been implicated in the silencing of ARHI. To investigate the mechanism of ARHI induction, MDA-MB-231 breast cancer cells were either transfected with the eukaryotic expression vector, pcDNA3.1(+)-ARHI, or were simultaneously treated with a histone deacetylase inhibitor, [trichostatin A, (TSA)] and the methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC). The latter treatment group also included the targeting of ARHI by small interfering RNA (siRNA) to further examine interactions between ARHI and the drugs applied. Levels of ARHI were detected by western blotting, MTT assays were used to evaluate cell proliferation, and both cell cycle progression and apoptosis were detected using flow cytometry. Both the transfection of pcDNA3.1(+)‑ARHI and the application of TSA+DAC induced the expression of ARHI. Furthermore, reduced cell proliferation, cell cycle arrest and enhanced apoptosis were observed for both groups compared to controls. However, a G1/S cell cycle arrest was observed for the pcDNA3.1(+)-ARHI group, while a G2 cell cycle arrest was observed for the TSA+DAC group. The latter effect was reversed with the introduction of ARHI-targeted siRNA in combination with TSA+DAC treatment. To further clarify these observations, expression levels of several key cell cycle regulators were analyzed by western blotting. The pcDNA3.1(+)-ARHI group exhibited higher expression levels of p53, p21 and p27, and lower levels of cyclin D1, CDK4 and CDK6 when compared to the control group (P<0.05). For the TSA+DAC group, higher levels of p53, p21, cyclin B1 and Chk1 were detected, concomitant with lower levels of CDK1, when compared to the control group. Taken together, these results suggest that ARHI acts as a tumor suppressor gene in MDA-MB-231 cells and, although TSA+DAC can block the cells at different cell cycle phage, the antitumor effect is ARHI-dependent.

Yang YL, Hung MS, Wang Y, et al.
Lung tumourigenesis in a conditional Cul4A transgenic mouse model.
J Pathol. 2014; 233(2):113-23 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

Wu X, Chen Y, Li G, et al.
Her3 is associated with poor survival of gastric adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway.
Med Oncol. 2014; 31(4):903 [PubMed] Related Publications
ErbB3 (Her3) is a membrane-bound protein which can form heterodimers with other EGF receptor family members with kinase activity. Previous reports identified Her3 as a significant predictor of poor survival in human gastric cancer (GC), but its mechanism has remained unclear. We sought to investigate the mechanism of Her3 in GC and its association with clinical characteristics. Her3 was detected by both real-time PCR and immunohistochemistry (IHC) in 161 GC patients, and its related downstream signaling PI3K/AKT activity and clinical characteristics were accessed by statistical analysis. Her3 siRNA was used in both in vitro and in vivo assay to investigate the mechanism. Her3 expression was significantly increased in human GC compared with adjacent normal gastric tissues as observed by both real-time PCR and IHC. Her3 expression was associated with downstream AKT activation and increased tumor size, metastasis and poor survival in GC patients. Knockdown of Her3 in human GC cell line can inhibit cell proliferation and tumor growth both in vitro and in vivo by inactivation of AKT. Her3 knockdown had no observed impact on Her2 expression or activity. G2/M arrest was investigated due to decreased CyclinB1 and p27(kip1) at T157. Increased apoptosis occurred in Her3 silenced GC cell treated with cisplatin due to decreased BAD at S112. Moreover, Her3 silence can inhibit cell migration in vitro and metastasis in vivo by down-regulating MMPs via PI3K/AKT signaling. Her3 is a new prognostic factor associated with tumor growth and metastasis via PI3K/AKT signaling.

Brognara E, Fabbri E, Bazzoli E, et al.
Uptake by human glioma cell lines and biological effects of a peptide-nucleic acids targeting miR-221.
J Neurooncol. 2014; 118(1):19-28 [PubMed] Related Publications
MicroRNAs are a family of small noncoding RNAs regulating gene expression by sequence-selective mRNA targeting, leading to a translational repression or mRNA degradation. The oncomiR miR-221 is highly expressed in human gliomas, as confirmed in this study in samples of low and high grade gliomas, as well in the cell lines U251, U373 and T98G. In order to alter the biological functions of miR-221, a peptide nucleic acid targeting miR-221 (R8-PNA-a221) was produced, bearing a oligoarginine peptide (R8) to facilitate uptake by glioma cells. The effects of R8-PNA-a221 were analyzed in U251, U373 and T98G glioma cells and found to strongly inhibit miR-221. In addition, the effects of R8-PNA-a221 on p27(Kip1) (a target of miR-221) were analyzed in U251 and T98G cells by RT-qPCR and by Western blotting. No change of p27(Kip1) mRNA content occurs in U251 cells in the presence of PNA-a221 (lacking the R8 peptide), whereas significant increase of p27(Kip1) mRNA was observed with the R8-PNA-a221. These data were confirmed by Western blot assay. A clear increment of p27(Kip1) protein expression in the samples treated with R8-PNA-a221 was detected. In addition, R8-PNA-a221 was found able to increase TIMP3 expression (another target of miR-221) in T98G cells. These results suggest that PNAs against oncomiRNA miR-221 might be proposed for experimental treatment of human gliomas.

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