CKS1B

Gene Summary

Gene:CKS1B; CDC28 protein kinase regulatory subunit 1B
Aliases: CKS1, ckshs1, PNAS-16, PNAS-18
Location:1q21.2
Summary:CKS1B protein binds to the catalytic subunit of the cyclin dependent kinases and is essential for their biological function. The CKS1B mRNA is found to be expressed in different patterns through the cell cycle in HeLa cells, which reflects a specialized role for the encoded protein. At least two transcript variants have been identified for this gene, and it appears that only one of them encodes a protein. [provided by RefSeq, Sep 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:cyclin-dependent kinases regulatory subunit 1
HPRD
Source:NCBIAccessed: 25 June, 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 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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

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

Latest Publications: CKS1B (cancer-related)

Zhao H, Bauzon F, Bi E, et al.
Substituting threonine 187 with alanine in p27Kip1 prevents pituitary tumorigenesis by two-hit loss of Rb1 and enhances humoral immunity in old age.
J Biol Chem. 2015; 290(9):5797-809 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
p27Kip1 (p27) is an inhibitor of cyclin-dependent kinases. Inhibiting p27 protein degradation is an actively developing cancer therapy strategy. One focus has been to identify small molecule inhibitors to block recruitment of Thr-187-phosphorylated p27 (p27T187p) to SCF(Skp2/Cks1) ubiquitin ligase. Since phosphorylation of Thr-187 is required for this recruitment, p27T187A knockin (KI) mice were generated to determine the effects of systemically blocking interaction between p27 and Skp2/Cks1 on tumor susceptibility and other proliferation related mouse physiology. Rb1(+/-) mice develop pituitary tumors with full penetrance and the tumors are invariably Rb1(-/-), modeling tumorigenesis by two-hit loss of RB1 in humans. Immunization induced humoral immunity depends on rapid B cell proliferation and clonal selection in germinal centers (GCs) and declines with age in mice and humans. Here, we show that p27T187A KI prevented pituitary tumorigenesis in Rb1(+/-) mice and corrected decline in humoral immunity in older mice following immunization with sheep red blood cells (SRBC). These findings reveal physiological contexts that depend on p27 ubiquitination by SCF(Skp2-Cks1) ubiquitin ligase and therefore help forecast clinical potentials of Skp2/Cks1-p27T187p interaction inhibitors. We further show that GC B cells and T cells use different mechanisms to regulate their p27 protein levels, and propose a T helper cell exhaustion model resembling that of stem cell exhaustion to understand decline in T cell-dependent humoral immunity in older age.

Chayka O, D'Acunto CW, Middleton O, et al.
Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells.
J Biol Chem. 2015; 290(4):2198-212 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.

Liu X, Wang W, Samarsky D, et al.
Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA.
Nucleic Acids Res. 2014; 42(18):11805-17 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-d-Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvβ3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.

Stella F, Pedrazzini E, Baialardo E, et al.
Quantitative analysis of CKS1B mRNA expression and copy number gain in patients with plasma cell disorders.
Blood Cells Mol Dis. 2014; 53(3):110-7 [PubMed] Related Publications
In this study, we have examined CKS1B gene expression and copy number in a total of 114- patients at diagnosis: 83 with multiple myeloma (MM) and 31 with monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with cytogenetics, FISH and clinical characteristic. Significant CKS1B mRNA levels in MM compared to MGUS cases (p<0.048) were detected. In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared to patients with normal karyotype (p=0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (p<0.0001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2 microglobulin in cases with 1q21 gains than those without (p=0.0094) was observed. Overall survival was shorter in cases with 1q21 gain compared to those with normal 1q21 region (p=0.0082). Our results suggest a role for CKS1B in the multiple step process of progression of MGUS to MM and show that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated to chromosome 1q alterations resulting in a more aggressive behavior of the disease.

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 27/02/2016 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.

Kim JY, Kim HJ, Park JH, et al.
Epidermal growth factor upregulates Skp2/Cks1 and p27(kip1) in human extrahepatic cholangiocarcinoma cells.
World J Gastroenterol. 2014; 20(3):755-73 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
AIM: To evaluate the expression status of S-phase kinase-associated protein 2 (Skp2)/cyclin-dependent kinases regulatory subunit 1 (Cks1) and p27(kip1), and assess the prognostic significance of Skp2/Cks1 expression with p27(kip1) in patients with extrahepatic cholangiocarcinoma.
METHODS: Seventy-six patients who underwent curative resection for histologically confirmed extrahepatic cholangiocarcinoma at our institution from December 1994 to March 2008 were enrolled. Immunohistochemical staining for Skp2, Cks1, p27(kip1), and Ki67, along with other relevant molecular biologic experiments, were performed.
RESULTS: By Cox regression analyses, advanced age (> 65 years), advanced AJCC tumor stage, poorly differentiated histology, and higher immunostaining intensity of Skp2 were identified as independent prognostic factors in patients with extrahepatic cholangiocarcinoma. Exogenous epidermal growth factor (EGF, especially 0.1-10 ng/mL) significantly increased the proliferation indices by MTT assay and the mRNA levels of Skp2/Cks1 and p27(kip1) in SNU-1196, SNU-1079, and SNU-245 cells. The protein levels of Skp2/Cks1 (from nuclear lysates) and p27(kip1) (from cytosolic lysate) were also significantly increased in these cells. There were significant reductions in the protein levels of Skp2/Cks1 and p27(kip1) (from nuclear lysate) after the treatment of LY294002. By chromatin immunoprecipitation assay, we found that E2F1 transcription factor directly binds to the promoter site of Skp2.
CONCLUSION: Higher immunostaining intensity of Skp2/Cks1 was an independent prognostic factor for patients with extrahepatic cholangiocarcinoma. EGF upregulates the mRNA and protein levels of Skp2/Cks1 and p27(kip1) via the PI3K/Akt pathway and direct binding of E2F1 transcription factor with the Skp2 promoter.

Bahmanyar M, Qi X, Chang H
Genomic aberrations in anaplastic multiple myeloma: high frequency of 1q21(CKS1B) amplifications.
Leuk Res. 2013; 37(12):1726-8 [PubMed] Related Publications
Anaplastic multiple myeloma (AMM) is a rare morphologic variant of MM with adverse prognosis. The underlying molecular cytogenetic abnormalities are poorly understood. We investigated 11 patients with AMM for myeloma associated cytogenetic aberrations and compared with 188 non-anaplastic MM using fluorescent in situ hybridization. Of the 11 AMM patients studied, 10 had CKS1B amplification, 5 hemizygous 17p(p53) deletions, 4 13q14 deletions, 4 t(4:14), and 2 had t(11:14). AMM was associated with significantly higher prevalence of CKS1B amplification (91% vs. 34%, p<0.001), 17p(p53) deletion (45% vs. 11%, p=0.006) and t(4,14) (36% vs. 14%, p=0.015) than non-anaplastic MM, which may have resulted in the genetic instability and more aggressive clinical course.

Jardim DL, Conley A, Subbiah V
Comprehensive characterization of malignant phyllodes tumor by whole genomic and proteomic analysis: biological implications for targeted therapy opportunities.
Orphanet J Rare Dis. 2013; 8:112 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
BACKGROUND: Phyllodes tumors are uncommon breast tumors that account for less than 0.5% of all breast malignancies. After metastases develop, the prognosis is poor, with very few patients living more than 1 year. The biology of this unusual cancer is not understood and, consequently, no potential targets for treatments are currently available. There has been an exponential increase in the number of commercially available tumor profiling services. Herein, we report a case of metastatic malignant phyllodes tumor for which a comprehensive molecular analysis was performed by using Clinical Laboratory Improvement Amendments (CLIA)-certified labs, providing new insights into the potential opportunities for molecularly targeted therapies for this extremely rare disease.
METHODS: Next-generation sequencing was performed by using the FoundationOne™ platform (Foundation Medicine, Cambridge, MA). Whole-genome array-based comparative genomic hybridization (array CGH) was performed by using the DNAarray™ (CombiMatrix Diagnostics, Irvine, CA). Immunohistochemical and morphoproteomics analysis were performed at Consultative proteomics®, The University of Texas, UT Health Medical School, Houston,TX (Robert E Brown Lab); Clarient Diagnostics, Aliso Viejo, CA; and Caris Life Sciences Target one, Irving, TX, USA.
RESULTS: Next-generation sequencing showed 3 aberrant genes: activating mutation Q61L on NRAS; inactivating mutations Q504* and K740* on RB1; and TP53 loss. Whole-genome array-based comparative genomic hybridization (array CGH) revealed amplifications of chromosome (chr.) 1 (CKS1B gene), chr. 8 (MYC gene), and chr. 9 (CDKN2A gene) Deletions of chr. 17 (TP53), chr. 10 (GATA3), chr. 11 (FGF4 and CCND1 genes), and chr.22 (PDGFβ). Immunohistochemical analysis for relevant markers showed a positive staining for transducing-like enhancer of split (TLE) 3; secreted protein acidic and rich in cysteine (SPARC) was expressed at 2-3+ in the cytoplasm of the tumors cells, whereas mammalian target of rapamycin (mTOR) was expressed up to 2+ in the nuclei of the tumor cells.
CONCLUSIONS: We describe for the first time an NRAS mutation with concomitant activation of PI3K/Akt/mTOR in phyllodes tumor. We also found markers for sensitivity to taxane-based therapies, especially albumin-bound paclitaxel. Exploring the biology of rare malignancies by CLIA certified labs may be reasonable strategy for the development of targeted treatments.

Lee SW, Lin CY, Tian YF, et al.
Overexpression of CDC28 protein kinase regulatory subunit 1B confers an independent prognostic factor in nasopharyngeal carcinoma.
APMIS. 2014; 122(3):206-14 [PubMed] Related Publications
Data mining on public domain identified that CDC28 protein kinase regulatory subunit 1B (CKS1B) transcript was highly expressed in nasopharyngeal carcinoma (NPC). The expression of CKS1B protein and its clinicopathological associations in patients with NPC were further evaluated. Immunoexpression of CKS1B was retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The correlations between CKS1B immunoexpression levels and clinicopathological features, as well as patient survivals, were analyzed. High CKS1B expression (49.2%) was correlated with the 7th American Joint Committee on Cancer (AJCC) stage (p = 0.014). In multivariate analyses, high CKS1B expression emerged as an independent prognostic factor for worse disease-specific survival (p < 0.001), metastasis-free survival (p < 0.001), and local recurrence-free survival (p = 0.001). High expression of CKS1B is common and associated with adverse prognostic factors and might confer tumor aggressiveness through dysregulation of the cyclin-dependent protein kinase (intrinsic regulatory activity) during cell cycle progression.

Buckley NE, Nic An tSaoir CB, Blayney JK, et al.
BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers.
Nucleic Acids Res. 2013; 41(18):8601-14 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue.

Li L, Chen DB, Lin C, et al.
hPNAS-4 inhibits proliferation through S phase arrest and apoptosis: underlying action mechanism in ovarian cancer cells.
Apoptosis. 2013; 18(4):467-79 [PubMed] Related Publications
PNAS-4, a novel pro-apoptotic gene, was activated during the early response to DNA damage. Previous studies have shown that hPNAS-4 can inhibit tumor growth when over-expressed in ovarian cancer cells. However, the underlying action mechanism remains elusive. In this work, we found that hPNAS-4 expression was significantly increased in SKOV3 cells when exposed to cisplatin, methyl methanesulfonate or mitomycin C, and that its overexpression could induce proliferation inhibition, S phase arrest and apoptosis in A2780s and SKOV3 ovarian cancer cells. The S phase arrest caused by hPNAS-4 was associated with up-regulation of p21. p21 is p53-dispensable and correlates with activation of ERK, and activation of the Cdc25A-Cdk2-Cyclin E/Cyclin A pathway, while the pro-apoptotic effects of hPNAS-4 were mediated by activation of caspase-9 and -3 other than caspase-8, and accompanied by release of AIF, Smac and cytochrome c into the cytosol. Taken together, these data suggest a new mechanism by which hPNAS-4 inhibits proliferation of ovarian cancer cells by inducing S phase arrest and apoptosis via activation of Cdc25A-Cdk2-Cyclin E/Cyclin A axis and mitochondrial dysfunction-mediated caspase-dependent and -independent apoptotic pathways. To our knowledge, we provide the first molecular evidence for the potential application of hPNAS-4 as a novel target in ovarian cancer gene therapy.

Wang JJ, Fang ZX, Ye HM, et al.
Clinical significance of overexpressed cyclin-dependent kinase subunits 1 and 2 in esophageal carcinoma.
Dis Esophagus. 2013 Sep-Oct; 26(7):729-36 [PubMed] Related Publications
The mammalian cyclin-dependent kinase subunit (Cks) family has two members, Cks1 and Cks2. Overexpression of Cks1 and Cks2 has been reported to be associated with high aggressiveness and poor prognosis in several malignancies, including prostate and hepatocellular carcinomas. However, whether Cks1 and Cks2 are overexpressed in esophageal carcinoma remains uncharacterized. To investigate whether overexpression of the Cks family is clinically relevant in esophageal carcinoma, and whether expression patterns of Cks1 and Cks2 can serve as biomarkers for esophageal carcinoma. Real-time quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and Western blot analyses were applied to detect the expression of Cks1 and Cks2 at the mRNA and protein levels, respectively. The associations between Cks1 or Cks2 expressions and clinical features and p27(kip1) expressions in esophageal carcinoma were analyzed. Comparing with the adjacent noncancerous tissues, esophageal carcinoma exhibited elevated expression of Cks1 in 58% cases at the mRNA level and 54% cases at the protein level, and elevated expression of Cks2 in 65% cases at the mRNA level and 61% cases at the protein level, respectively. The expressions of both Cks1 and Cks2 were negatively associated with the p27(kip1) protein level in the tumor tissues. Furthermore, overexpression of Cks1 and Cks2 in esophageal carcinoma was closely associated with poor pathological features of esophageal carcinoma, including higher histologic grade of tumor, regional lymph nodes invasion, and neoplastic embolus. Overexpression of Cks1 and Cks2 is associated with the aggressive tumor behaviors of esophageal carcinoma. Further efforts are needed to determine whether overexpression of Cks1 and Cks2 can serve as novel biomarkers for esophageal carcinoma.

Thomas SM, Sahu B, Rapireddy S, et al.
Antitumor effects of EGFR antisense guanidine-based peptide nucleic acids in cancer models.
ACS Chem Biol. 2013; 8(2):345-52 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
Peptide nucleic acids have emerged over the past two decades as a promising class of nucleic acid mimics because of their strong binding affinity and sequence selectivity toward DNA and RNA, and resistance to enzymatic degradation by proteases and nucleases. While they have been shown to be effective in regulation of gene expression in vitro, and to a small extent in vivo, their full potential for molecular therapy has not yet been fully realized due to poor cellular uptake. Herein, we report the development of cell-permeable, guanidine-based peptide nucleic acids targeting the epidermal growth factor receptor (EGFR) in preclinical models as therapeutic modality for head and neck squamous cell carcinoma (HNSCC) and nonsmall cell lung cancer (NSCLC). A GPNA oligomer, 16 nucleotides in length, designed to bind to EGFR gene transcript elicited potent antisense effects in HNSCC and NSCLC cells in preclinical models. When administered intraperitoneally in mice, EGFRAS-GPNA was taken-up by several tissues including the xenograft tumor. Systemic administration of EGFRAS-GPNA induced antitumor effects in HNSCC xenografts, with similar efficacies as the FDA-approved EGFR inhibitors: cetuximab and erlotinib. In addition to targeting wild-type EGFR, EGFRAS-GPNA is effective against the constitutively active EGFR vIII mutant implicated in cetuximab resistance. Our data reveals that GPNA is just as effective as a molecular platform for treating cetuximab resistant cells, demonstrating its utility in the treatment of cancer.

Dibb M, Han N, Choudhury J, et al.
The FOXM1-PLK1 axis is commonly upregulated in oesophageal adenocarcinoma.
Br J Cancer. 2012; 107(10):1766-75 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
BACKGROUND: The transcription factor FOXM1 is an important regulator of the cell cycle through controlling periodic gene expression during the G2 and M phases. One key target for FOXM1 is the gene encoding the protein kinase PLK1 and PLK1 itself acts in a positive feedback loop to phosphorylate and activate FOXM1. Both FOXM1 and PLK1 have been shown to be overexpressed in a variety of different tumour types.
METHODS: We have used a combination of RT-PCR, western blotting, tissue microarrays and metadata analysis of microarray data to study whether the FOXM1-PLK1 regulatory axis is upregulated and operational in oesophageal adenocarcinoma.
RESULTS: FOXM1 and PLK1 are expressed in oesophageal adenocarcinoma-derived cell lines and demonstrate cross-regulatory interactions. Importantly, we also demonstrate the concomitant overexpression of FOXM1 and PLK1 in a large proportion of oesophageal adenocarcinoma samples. This co-association was extended to the additional FOXM1 target genes CCNB1, AURKB and CKS1. In a cohort of patients who subsequently underwent surgery, the expression of several FOXM1 target genes was prognostic for overall survival.
CONCLUSIONS: FOXM1 and its target gene PLK1 are commonly overexpressed in oesophageal adenocarcinomas and this association can be extended to other FOXM1 target genes, providing potentially important biomarkers for predicting post-surgery disease survival.

Huang KT, Pavlides SC, Lecanda J, et al.
Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer.
PLoS One. 2012; 7(9):e46072 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
The levels of proteins that control the cell cycle are regulated by ubiquitin-mediated degradation via the ubiquitin-proteasome system (UPS) by substrate-specific E3 ubiquitin ligases. The cyclin-dependent kinase inhibitor, p27kip1 (p27), that blocks the cell cycle in G1, is ubiquitylated by the E3 ligase SCF-Skp2/Cks1 for degradation by the UPS. In turn, Skp2 and Cks1 are ubiquitylated by the E3 ligase complex APC/Cdh1 for destruction thereby maintaining abundant levels of nuclear p27. We previously showed that perpetual proteasomal degradation of p27 is an early event in Type I endometrial carcinogenesis (ECA), an estrogen (E2)-induced cancer. The present studies demonstrate that E2 stimulates growth of ECA cell lines and normal primary endometrial epithelial cells (EECs) and induces MAPK-ERK1/2-dependent phosphorylation of p27 on Thr187, a prerequisite for p27 ubiquitylation by nuclear SCF-Skp2/Cks1 and subsequent degradation. In addition, E2 decreases the E3 ligase [APC]Cdh1 leaving Skp2 and Cks1 intact to cause p27 degradation. Furthermore, knocking-down Skp2 prevents E2-induced p27 degradation and growth stimulation suggesting that the pathogenesis of E2-induced ECA is dependent on Skp2-mediated degradation of p27. Conversely, progesterone (Pg) as an inhibitor of endometrial proliferation increases nuclear p27 and Cdh1 in primary EECs and ECA cells. Pg, also increases Cdh1 binding to APC to form the active E3ligase. Knocking-down Cdh1 obviates Pg-induced stabilization of p27 and growth inhibition. Notably, neither E2 nor Pg affected transcription of Cdh1, Skp2, Cks1 nor p27. These studies provide new insights into hormone regulation of cell proliferation through the UPS. The data implicates that preventing nuclear p27 degradation by blocking Skp2/Cks1-mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA.

Miyai K, Yamamoto S, Iwaya K, et al.
Altered expression of p27(Kip1) -interacting cell-cycle regulators in the adult testicular germ cell tumors: potential role in tumor development and histological progression.
APMIS. 2012; 120(11):890-900 [PubMed] Related Publications
We examined the potential role of cell-cycle dysregulation in the development and histological progression of adult testicular germ cell tumors (TGCTs). Expressions of p27(Kip1) -interacting cell-cycle regulators (down-regulation of p27(Kip1) and overexpression of Skp2, Cks1, cyclin A, and cyclin E) and Ki-67 labeling index (LI) were immunohistochemically examined in histological components of 50 intratubular germ cell neoplasms, unclassified (IGCNUs); 74 seminomas; and 25 embryonal carcinomas, identified from 88 patients. Altered expression of p27(Kip1) , Skp2, Cks1, cyclin A, and cyclin E was observed in 20%, 12%, 16%, 10%, and 24% of IGCNUs; 26%, 36%, 27%, 89%, and 23% of seminomas; and 48%, 68%, 56%, 100%, and 60% of embryonal carcinomas, respectively. A significant difference in the frequency of Skp2 and cyclin A overexpression was observed between IGCNUs and seminomas. Significantly more frequent alterations of Skp2, Cks1, and cyclin E and p27(Kip1) were detected in embryonal carcinomas than in seminomas. Alterations of all cell-cycle regulators were significantly more frequent in embryonal carcinomas than in IGCNUs. The mean Ki-67 LI significantly increased from IGCNU (21.2%) through seminoma (34.7%) to embryonal carcinoma (54.2%). These results suggest that alterations of the p27(Kip1) -interacting cell-cycle regulators are common in TGCTs and may be involved in their histological progression.

Zhu Y, Xiao X, Dong L, Liu Z
Differentially expressed proteins identified in overexpressed let-7a gastric carcinoma cells by two-dimensional polyacrylamide gel electrophoresis.
Tumour Biol. 2012; 33(5):1281-90 [PubMed] Related Publications
MicroRNAs are small noncoding RNA molecules that control the expression of target genes. Our previous studies show that let-7a decreased in gastric carcinoma and that up-regulation of let-7a by gene augmentation inhibited gastric carcinoma cell growth both in vitro and in vivo, whereas it remains largely unclear as to how let-7a affects tumor growth. In this study, proteins associated with the function of let-7a were detected in high-throughput screening. The cell line of SGC-7901 stably overexpressing let-7a was successfully established by gene clone. Two-dimensional gel electrophoresis (2-DE) was used to separate the total proteins of SGC-7901/let-7a, SGC-7901/EV and SGC-7901, and PDQuest software was applied to analyze 2-DE images. Ten differential protein spots were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and they may be the proteins associated with let-7a function. The overexpressed proteins include antioxidant protein 2, insulin-like growth factor binding protein 2, protein disulfide isomerase A2, C-1-tetrahydrofolate synthase, cyclin-dependent kinase inhibitor1 (CDKN1) and Rho-GTPase activating protein 4. The underexpressed proteins consisted of S-phase kinase-associated protein 2 (Spk2), platelet membrane glycoprotein, fibronectin and Cks1 protein. Furthermore, the different expression levels of the partial proteins (CDKN1,Spk2 and Fibronectin) were confirmed by Western blot analysis. The data suggest that these differential proteins are involved in novel let-7a signal pathway, and these findings provided the basis to comprehensively investigate the functional mechanisms of let-7a in gastric carcinoma.

Zhu Y, Xiao X, Dong L, Liu Z
Investigation and identification of let-7a related functional proteins in gastric carcinoma by proteomics.
Anal Cell Pathol (Amst). 2012; 35(4):285-95 [PubMed] Related Publications
MicroRNAs are small noncoding RNA molecules that control expression of target genes. Our previous studies show that let-7a decreased in gastric carcinoma and that up-regulation of let-7a by gene augmentation inhibited gastric carcinoma cell growth both in vitro and in vivo, whereas it remains largely unclear as to how let-7a affects tumor growth. In this study, proteins associated with the function of let-7a were detected by high throughout screening. The cell line of SGC-7901 stablely overexpressing let-7a was successfully established by gene cloning. Two-dimensional gel electrophoresis (2-DEy was used to separate the total proteins of SGC-7901/let-7a, SGC-7901/EV and SGC-7901, and PDQuest software was applied to analyze 2-DE images. Ten different protein spots were identified by MALDI-TOF-MS, and they may be the proteins associated with let-7a function. The overexpressed proteins included Antioxidant protein 2, Insulin-like growth factor binding protein 2, Protein disulfide isomerase A2, C-1-tetrahydrofolate synthase, Cyclin-dependent kinase inhibitor1 (CDKN1) and Rho-GTPase activating protein 4. The underexpressed proteins consisted of S-phase kinase-associated protein 2 (Spk2), Platelet membrane glycoprotein, Fibronectin and Cks1 protein. Furthermore, the different expression levels of the partial proteins (CDKN1, Spk2 and Fibronectin) were confirmed by western blot analysis. The data suggest that these differential proteins are involved in a novel let-7a signal pathway and these findings provide the basis to investigate the functional mechanisms of let-7a in gastric carcinoma.

Tonelli R, McIntyre A, Camerin C, et al.
Antitumor activity of sustained N-myc reduction in rhabdomyosarcomas and transcriptional block by antigene therapy.
Clin Cancer Res. 2012; 18(3):796-807 [PubMed] Related Publications
PURPOSE: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription.
EXPERIMENTAL DESIGN: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined.
RESULTS: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity.
CONCLUSION: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo.

Chen MH, Qi C, Reece D, Chang H
Cyclin kinase subunit 1B nuclear expression predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with bortezomib.
Hum Pathol. 2012; 43(6):858-64 [PubMed] Related Publications
Amplification of cyclin kinase subunit 1B gene on chromosome 1q21 resulting in overexpression of cyclin kinase subunit 1B has been associated with disease progression in multiple myeloma. Bortezomib is a proteasome inhibitor that induces apoptosis in various cancer cells and has been shown to be effective as a salvage therapy for relapsed/refractory multiple myeloma. Our group has recently reported the adverse effect of 1q21 gains in relapsed and refractory multiple myeloma treated with bortezomib. However, whether nuclear cyclin kinase subunit 1B protein expression correlates with 1q21 gains and has prognostic value in patients with multiple myeloma receiving bortezomib regimen remains unclear. We, therefore, evaluated the nuclear expression of cyclin kinase subunit 1B protein in patients with relapsed/refractory multiple myeloma undergoing bortezomib therapy by immunohistochemistry. The 1q21 amplification status of the same cohort was examined by interphase cytoplasmic immunoglobulin fluorescence in situ hybridization. Of 60 cases, 19 (32%) were positive for cyclin kinase subunit 1B nuclear expression by immunohistochemistry. Seventeen (89%) of the immunohistochemistry-positive cases had 1q21 gain detected by cytoplasmic immunoglobulin fluorescence in situ hybridization, and 17 (77%) of the 22 cases with 1q21 gain showed increased cyclin kinase subunit 1B protein expression. cyclin kinase subunit 1B expression and 1q21 gain were strongly correlated (P < .0001). There was no significant difference in response rate between patients with and without cyclin kinase subunit 1B nuclear expression. However, patients with cyclin kinase subunit 1B expression had a significantly shorter progression-free survival (1.9 versus 5.6 months; P < .0001) and overall survival (4.9 versus 22.4 months; P = .012) compared with those without cyclin kinase subunit 1B expression. Our results indicated that cyclin kinase subunit 1B nuclear expression detected by immunohistochemistry is an adverse prognostic factor for patients with multiple myeloma treated with bortezomib therapy.

Kim HJ, Lee KY, Kim YC, et al.
Detection and comparison of peptide nucleic acid-mediated real-time polymerase chain reaction clamping and direct gene sequencing for epidermal growth factor receptor mutations in patients with non-small cell lung cancer.
Lung Cancer. 2012; 75(3):321-5 [PubMed] Related Publications
EGFR tyrosine kinase inhibitors (EGFR-TKIs) are recommended as first-line therapy in patients with advanced, recurrent, or metastatic non-squamous non-small cell lung cancer (NSCLC) that have active EGFR mutations. The importance of rapid and sensitive methods for the detection of EGFR mutations is emphasized. The aim of this study is to examine the EGFR mutational status by both direct DNA sequencing and peptide nucleic acid (PNA)-mediated real-time PCR clamping and to evaluate the correlation between the EGFR mutational status and the clinical response to EGFR-tyrosine kinase inhibitors. Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of the Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA was extracted from paraffin-embedded tissue specimens, we performed PNA-mediated real-time PCR clamping and direct DNA sequencing for the detection of EGFR mutations. Of 240 tumor samples, PNA-mediated PCR clamping was used to detect genomic alterations in 83 (34.6%) samples, including 61 identified by sequencing and 22 additional samples (10 in exon 19, 9 in exon 21, and 3 in both exons); direct DNA sequencing was used to identify a total of 63 (26.3%) mutations that contained 40 deletion mutations in exon 19 (63.5%) and 18 substitution mutations (28.6%) in exon 21. PNA-mediated PCR clamping was used to identify more mutations than clinical direct sequencing, whereas clinical outcomes were not significantly different between the groups harboring activating mutations detected by each method. These data suggest that PNA-mediated real-time PCR clamping exhibits high sensitivity and is a simple procedure relative to direct DNA sequencing that is a useful screening tool for the detection of EGFR mutations in clinical settings.

Lee EK, Kim DG, Kim JS, Yoon Y
Cell-cycle regulator Cks1 promotes hepatocellular carcinoma by supporting NF-κB-dependent expression of interleukin-8.
Cancer Res. 2011; 71(21):6827-35 [PubMed] Related Publications
The cell-cycle regulator Cks1 has recently been implicated in Skp2-mediated ubiquitination of the tumor suppressor protein p27. In this article, we report that Cks1 exerts a Skp2-independent regulation of NF-κB that promotes interleukin-8 (IL-8) expression, which is critical to hepatocellular carcinoma (HCC) growth. Cks1 was upregulated frequently in human HCC tissues and cell lines. Cks1 knockdown in HCC cells elevated p27 levels and decreased tumorigenicity in a manner that was also associated with a strong downregulation of IL-8 expression. IL-8 downregulation was not phenocopied by either RNAi-mediated knockdown of Skp2 or ectopic overexpression of p27. However, attenuation of IL-8 expression itself was sufficient to blunt HCC growth. Mechanistic investigations revealed that IL-8 was controlled at a transcriptional level by Cks1 targeting of the NF-κB regulator IκBα, which led to NF-κB activation and IL-8 expression, through a p27-independent regulation of IκB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-κB-mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination.

Hatakeyama H, Akita H, Ito E, et al.
Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid.
Biomaterials. 2011; 32(18):4306-16 [PubMed] Related Publications
Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment. In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEG-unmodified MEND due to less accumulation in liver and spleen.

Ha YS, Yan C, Kim IY, et al.
Tissue hOGG1 genotype predicts bladder cancer prognosis: a novel approach using a peptide nucleic acid clamping method.
Ann Surg Oncol. 2011; 18(6):1775-81 [PubMed] Related Publications
BACKGROUND: Tissue genotyping is a more useful approach than using blood genomic DNA, because the tumor tissues can reflect the effects of somatic mutations in cancer. We investigated the value of the human oxoguanine glycosylase (hOGG1) genotype determined in tumor tissues as a prognostic indicator for bladder cancer (BC) using a novel technological approach.
METHODS: A total of 335 DNA samples from patients with primary BC were analyzed by peptide nucleic acid (PNA)-mediated real-time polymerase chain reaction (PCR) clamping to characterize the association between genetic polymorphisms within hOGG1 codon 326 and the clinicopathological characteristics of primary BC patients.
RESULTS: Tumor stage and number were significantly associated with the hOGG1 codon 326 genotype in nonmuscle invasive bladder cancer (NMIBC) patients. Compared with Cys326Ser and Ser326Ser, the Cys326Cys genotype had a greater progression-free survival benefit in patients with muscle invasive bladder cancer (MIBC). Univariate and multivariate Cox regression analyses indicated that the hOGG1 Cys326Cys genotype has a protective effect against progression in MIBC (hazard ratio, 0.360 and 0.314, respectively).
CONCLUSIONS: The hOGG1 tissue genotype is associated with aggressive clinicopathological features in NMIBC and with progression in patients with MIBC. Results suggest that the hOGG1 tissue genotype represents a promising marker for assessing BC prognosis in the clinical setting.

Martín-Ezquerra G, Salgado R, Toll A, et al.
CDC28 protein kinase regulatory subunit 1B (CKS1B) expression and genetic status analysis in oral squamous cell carcinoma.
Histol Histopathol. 2011; 26(1):71-7 [PubMed] Related Publications
CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) protein family which interacts with cyclin-dependent kinases and plays a critical role in cell cycle progression. In oral squamous cell carcinoma (OSCC), as in other malignancies, CKS1B overexpression has been correlated with reduced survival. To our knowledge, no studies evaluating the genetic status of CKS1B gene in OSCC have been reported. Herein, genetic and protein status of CKS1B were analyzed by immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) techniques in a series of primary OSCC (n=51) and lymph node OSCC metastases samples (n=14). The observed results were compared with those obtained in either inflammatory (oral lichen planus [OLP]) (n=13) and premalignant oral mucosal lesions (oral leukoplakia) (n=16). A significant CKS1B overexpression was observed in OSCC and lymph node metastases samples than in OLP and oral leukoplakia (mean 70% vs 35%, p<0.001). CKS1B overexpression correlated with p27 loss of expression (p=0.0013) and SKP2 overexpression (p<0.00). FISH study disclosed statistical differences in both gene amplifications and gains between samples corresponding to OSCC and metastases from those of OLP and leukoplakia (p<0.001). Amplifications were present in 53% of OSCC samples and 33% of lymph node metastases vs 14% of oral leukoplakia and 0% of OLP biopsy specimens (p=0.002). Polysomies of chromosome 1 were seen in 46% of OSCC, 33% of ganglionar metastases, 14% of oral leukoplakia and 10% of OLP (p=0.036). Correlation of CKS1B over-expression and gains (both polysomies and amplifications) determined by FISH was statistically significant (p<0.001). Our results indicate that a high CKS1B expression is a common finding in primary OSCC which correlates with p27 low expression and SKP2 overexpression. This phenomenon may be due either to numerical (chromosome 1 polysomy) or structural (amplifications) CKS1B genetic abnormalities. This phenotypical and cytogenetic profile is not observed in premalignant or inflammatory oral mucosal lesions.

Jiang J, Sliva D
Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells.
Int J Oncol. 2010; 37(6):1529-36 [PubMed] Related Publications
Mushrooms are an integral part of Traditional Chinese Medicine (TCM), and have been used for millennia to prevent or treat a variety of diseases. Currently mushrooms or their extracts are used globally in the form of dietary supplements. In the present study we have evaluated the anticancer effects of the dietary supplement, MycoPhyto® Complex (MC), a novel medicinal mushroom blend which consists of a blend of mushroom mycelia from the species Agaricus blazei, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa and Polyporus umbellatus, and β-1,3-glucan isolated from the yeast, Saccharomyces cerevisiae. Here, we show that MC demonstrates cytostatic effects through the inhibition of cell proliferation and cell cycle arrest at the G2/M phase of highly invasive human breast cancer cells MDA-MB-231. DNA-microarray analysis revealed that MC inhibits expression of cell cycle regulatory genes (ANAPC2, ANAPC2, BIRC5, Cyclin B1, Cyclin H, CDC20, CDK2, CKS1B, Cullin 1, E2F1, KPNA2, PKMYT1 and TFDP1). Moreover, MC also suppresses the metastatic behavior of MDA-MB-231 by the inhibition of cell adhesion, cell migration and cell invasion. The potency of MC to inhibit invasiveness of breast cancer cells is linked to the suppression of secretion of the urokinase plasminogen activator (uPA) from MDA-MB-231 cells. In conclusion, the MC dietary supplement could have potential therapeutic value in the treatment of invasive human breast cancer.

Shi L, Wang S, Zangari M, et al.
Over-expression of CKS1B activates both MEK/ERK and JAK/STAT3 signaling pathways and promotes myeloma cell drug-resistance.
Oncotarget. 2010; 1(1):22-33 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
Here we demonstrate the crucial role of CKS1B in multiple myeloma (MM) progression and define CKS1B-mediated SKP2/p27(Kip1)-independent down-stream signaling pathways. Forced-expression of CKS1B in MM cells increased cell multidrug-resistance. CKS1B activates STAT3 and MEK/ERK pathways. In contrast, SKP2 knockdown or p27(Kip1) over-expression resulted in activation of the STAT3 and MEK/ERK pathways. Further investigations showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3 and MEK/ERK signaling pathways partially abrogated CKS1B knockdown induced MM cell death and growth inhibition. Targeting STAT3 and MEK/ERK signaling pathways by specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-overexpressing MM cells and their combinations resulted in synergy. Thus, our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in aggressive CKS1B-overexpressing MM.

Salgado R, Toll A, Alameda F, et al.
CKS1B amplification is a frequent event in cutaneous squamous cell carcinoma with aggressive clinical behaviour.
Genes Chromosomes Cancer. 2010; 49(11):1054-61 [PubMed] Related Publications
Genetic mechanisms giving rise to the development of cutaneous squamous cell carcinoma (cSCC) are poorly understood and development of genomic high resolution techniques has led to a better knowledge of the genetic basis of several human cancers. In this study, 16 cSCC were analyzed using array comparative genomic hybridization (arrayCGH). The most common aberrations found were gains of 3q11q13, 1q21.3q25, 13q34, and 19p13, and losses of 1p36p31, 3p24p21, 10p15q22, and 13q11q21. We detected gains (3/16) and amplification (1/16) of the 1q21.1q21.3 region. A potential candidate gene in this region, CKS1B (1q21.2), was selected for validation in an independent cohort and correlations with clinicopathological features were carried out. CKS1B gene and protein status were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in a series of 53 cSCC, 22 actinic keratoses (AK), and 10 normal skin samples. cSCC presented a higher frequency of chromosome 1 polysomy than AK (70% vs. 46%, P = 0.047). Association between CKS1B protein overexpression and both polysomy and amplification was demonstrated in cSCC (P < 0.001). Regarding amplifications, 11 cSCC patients (21%) presented CKS1B gene amplification. Interestingly, 8/11 (73%) patients who showed a CKS1B amplification had presented metastatic spread (mcSCC). Differences between the presence of CKS1B amplification and the presence or absence of mcSCC were observed (mcSCC [8/14] vs. cSCC [3/39]) (P < 0.001). Several drugs targeting CKS1B have been reported and may be useful for treating patients with cSCC and CKS1B amplifications.

Akyurek N, Drakos E, Giaslakiotis K, et al.
Differential expression of CKS-1B in typical and blastoid variants of mantle cell lymphoma.
Hum Pathol. 2010; 41(10):1448-55 [PubMed] Related Publications
Mantle cell lymphoma is a distinct type of B-cell lymphoma characterized by the t(11;14)(q13;q32). Mantle cell lymphomas exhibit a spectrum of morphologic findings, of which a subset of tumors is clinically aggressive with a high proliferation rate. These neoplasms are known as aggressive variants of which there are blastoid and pleomorphic subsets. CKS-1B (CDC28 protein kinase regulatory subunit 1B) is essential for the ubiquitination and degradation of p27 and cell cycle progression. We analyzed CKS-1B expression in mantle cell lymphoma cell lines and tumors by Western blot and immunohistochemical analysis. In 4 mantle cell lymphoma cell lines, CKS-1B was expressed at variable levels and correlated inversely with p27 expression. In mantle cell lymphoma tumors, CKS-1B was positive in 10 (28.6%) of 35 typical versus 14 (87.5%) of 16 blastoid/pleomorphic cases (Fisher exact test, P = .0002). Analyzed as a continuous variable, the percentage of CKS-1B-positive cells significantly correlated with blastoid/pleomorphic morphology (Mann-Whitney U test, P = .001). Twelve (23.5%) of 51 mantle cell lymphoma tumors expressed p27. Proliferation rate (Ki-67) was higher in blastoid/pleomorphic variants than in typical mantle cell lymphoma tumors and was inversely associated with p27 levels in typical mantle cell lymphoma. However, CKS-1B expression did not correlate with p27 expression, proliferation rate, or prognosis in the entire study group. Fluorescence in situ hybridization analysis of 10 CKS-1B-positive mantle cell lymphoma tumors showed no evidence of CKS-1B gene amplification. We conclude that CKS-1B is commonly expressed in mantle cell lymphoma, particularly in aggressive histologic variants, and may be involved in pathogenesis.

Chen L, Chan TH, Guan XY
Chromosome 1q21 amplification and oncogenes in hepatocellular carcinoma.
Acta Pharmacol Sin. 2010; 31(9):1165-71 [PubMed] Article available free on PMC after 27/02/2016 Related Publications
Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. During human multistep hepatocarcinogenesis, genomic gain represents an important mechanism in the activation of proto-oncogenes. In many circumstances, activated oncogenes hold clinical implications both as prognostic markers and targets for cancer therapeutics. Gain of chromosome 1q copy is one of the most frequently detected alterations in HCC and 1q21 is the most frequent minimal amplifying region (MAR). A better understanding of the physiological and pathophysiological roles of target genes within 1q21 amplicon will significantly improve our knowledge in HCC pathogenesis, and may lead to a much more effective management of HCC bearing amplification of 1q21. Such knowledge has long term implications for the development of new therapeutic strategies for HCC treatment. Our research group and others, focused on the identification and characterization of 1q21 target genes such as JTB, CKS1B, and CHD1L in HCC progression. In this review, we will summarize the current scientific knowledge of known target genes within 1q21 amplicon and the precise oncogenic mechanisms of CHD1L will be discussed in detail.

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