Gene Summary

Gene:KL; klotho
Summary:This gene encodes a type-I membrane protein that is related to beta-glucosidases. Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, mutations within this protein have been associated with ageing and bone loss. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 11 March, 2017


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 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 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: KL (cancer-related)

Ren HT, Li YM, Wang XJ, et al.
PD-1 rs2227982 Polymorphism Is Associated With the Decreased Risk of Breast Cancer in Northwest Chinese Women: A Hospital-Based Observational Study.
Medicine (Baltimore). 2016; 95(21):e3760 [PubMed] Free Access to Full Article Related Publications
Programmed death-1 (PD-1) is crucial in cancer and is well characterized as a negative T-cell regulator that functions by delivering inhibitory signals. We aimed to evaluate the relationship between PD-1 polymorphisms (rs10204525, rs2227982, and rs7421861) and breast cancer risk.We selected 560 breast cancer patients and 583 age-, sex-, and ethnicity-matched healthy controls from Northwest China. The PD-1 polymorphisms were genotyped by using Sequenom MassARRAY. Associations were estimated with odds ratios (ORs) and 95% confidence intervals (95% CIs).For the rs10204525 and rs7421861 polymorphisms, no differences in breast cancer risk were found in any of the genetic models. For the rs2227982 polymorphism, the variant genotypes were significantly associated with decreased breast cancer risk (CT vs CC: OR = 0.68, 95% CI = 0.52-0.91; CT + TT vs CC: OR = 0.69, 95% CI = 0.53-0.90). In analyses stratified by age, the decreased risk was observed among the younger subjects (OR = 0.68, 95% CI = 0.47-0.97). We found that the decreased risk observed for the variant genotypes of rs2227982 was associated with the Her-2 status (CT vs CC: OR = 0.55, 95% CI = 0.37-0.84; CT + TT vs CC: OR = 0.56, 95% CI = 0.38-0.82). The haplotype analysis showed that the Ars10204525 Trs2227982 Crs7421861 haplotype was associated with a significantly decreased risk of breast cancer (OR = 0.50, 95% CI = 0.34-0.75).Our findings support an association between the PD-1 rs2227982 polymorphism and decreased breast cancer risk, especially in Her-2 positive breast cancer patients in the Chinese population.

Dai ZM, Kang HF, Zhang WG, et al.
The Associations of Single Nucleotide Polymorphisms in miR196a2, miR-499, and miR-608 With Breast Cancer Susceptibility: A STROBE-Compliant Observational Study.
Medicine (Baltimore). 2016; 95(7):e2826 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play an important role as regulators of tumor suppressors and oncogenes in cancer-related processes. Single nucleotide polymorphisms (SNPs) in miRNAs have been shown to be relevant to various different cancers, including breast cancer (BC). The aim of this study was to estimate the associations between miRNA-related gene polymorphisms (miR-196a2, miR-499, and miR-608) and the risk of BC in a Chinese population. Gene polymorphisms were analyzed in 1143 subjects (controls = 583; BC = 560). The 3 SNPs were genotyped using the Sequenom Mass-ARRAY platform. The associations between the SNP frequencies and BC were assessed by computing odds ratios (ORs) and 95% confidence intervals (95% CIs), as well as by applying Chi-square tests. The miR-196a2 (rs11614913) T allele was associated with a decreased risk of BC based on results from dominant (OR = 0.67, 95% CI = 0.52-0.86), recessive (OR = 0.65, 95% CI = 0.48-0.86), and allele models (OR = 0.73, 95% CI = 0.62-0.86). In contrast, the miR-499 (rs3746444) AG/GG genotypes were associated with an increased risk of BC (OR = 1.45, 95% CI = 1.10-1.91), and miR-608 (rs4919510) was not significantly associated with BC risk. Our study suggested that the polymorphisms of rs11614913 and rs3746444 may be associated with BC risk in Chinese individuals.

Dai ZJ, Liu XH, Ma YF, et al.
Association Between Single Nucleotide Polymorphisms in DNA Polymerase Kappa Gene and Breast Cancer Risk in Chinese Han Population: A STROBE-Compliant Observational Study.
Medicine (Baltimore). 2016; 95(2):e2466 [PubMed] Free Access to Full Article Related Publications
DNA polymerases are responsible for ensuring stability of the genome and avoiding genotoxicity caused by a variety of factors during DNA replication. Consequently, these proteins have been associated with an increased cancer risk. DNA polymerase kappa (POLK) is a specialized DNA polymerase involved in translesion DNA synthesis (TLS) that allows DNA synthesis over the damaged DNA. Recently, some studies investigated relationships between POLK polymorphisms and cancer risk, but the role of POLK genetic variants in breast cancer (BC) remains to be defined. In this study, we aimed to evaluate the effects of POLK polymorphisms on BC risk.We used the Sequenom MassARRAY method to genotype 3 single nucleotide polymorphisms (SNPs) in POLK (rs3213801, rs10077427, and rs5744533), in order to determine the genotypes of 560 BC patients and 583 controls. The association of genotypes and BC was assessed by computing the odds ratio (OR) and 95% confidence intervals (95% CIs) from logistic regression analyses.We found a statistically significant difference between patient and control groups in the POLK rs10077427 genotypic groups, excluding the recessive model. A positive correlation was also found between positive progesterone receptor (PR) status, higher Ki67 index, and rs10077427 polymorphism. For rs5744533 polymorphism, the codominant, dominant, and allele models frequencies were significantly higher in BC patients compared to healthy controls. Furthermore, our results indicated that rs5744533 SNP has a protective role in the postmenopausal women. However, we failed to find any associations between rs3213801 polymorphism and susceptibility to BC.Our results indicate that POLK polymorphisms may influence the risk of developing BC, and, because of this, may serve as a prognostic biomarker among Chinese women.

Sahm F, Schrimpf D, Olar A, et al.
TERT Promoter Mutations and Risk of Recurrence in Meningioma.
J Natl Cancer Inst. 2016; 108(5) [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher's exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.

Asim M, Massie CE, Orafidiya F, et al.
Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target.
J Natl Cancer Inst. 2016; 108(5) [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.
METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.
RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.
CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

Zhang Y, Wang J, Sui X, et al.
Prognostic and Clinicopathological Value of Survivin in Diffuse Large B-cell Lymphoma: A Meta-Analysis.
Medicine (Baltimore). 2015; 94(36):e1432 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Up to date, survivin, a well-known inhibitor of apoptosis, has attracted considerable attention as a potential biomarker and therapeutic target in diffuse large B-cell lymphoma (DLBCL). Nevertheless, there still remains no consensus on heterogeneous results. Herein, a meta-analysis was performed to clarify a convincing significance of survivin status on prognosis and clinicopathology of DLBCL patients.Eligible studies were identified by searching Medline, Embase, Scopus, CNKI, and Wanfang databases (last updated on November 30, 2014). Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Heterogeneity and sensitivity were also analyzed. Moreover, Begg, Egger test, and funnel plots were applied to evaluate the publication bias.We finally included 17 eligible studies with the total number of 1352 patients in the meta-analysis. The pooled results showed that positive survivin expression in DLBCL was associated with inferior overall survival (OS) (HR: 1.880, 95% CI: 1.550-2.270) in patients. Moreover, a significant association was revealed between survivin expression and advanced clinical stage (III + IV) (OR: 0.611, 95% CI: 0.452-0.827), higher International Prognosis Index (IPI) score (Score 3-5) (OR: 0.559; 95% CI: 0.410-0.761), elevated serum lactic dehydrogenase (LDH) (OR: 0.607, 95% CI: 0.444-0.831), presence of bone marrow involvement (OR: 2.127, 95% CI: 1.154-3.921) together with reduced complete remission (CR) rate (OR: 0.478, 95% CI: 0.345-0.662).The results suggest that survivin could be a useful prognostic biomarker, and a promising target for DLBCL therapeutic intervention. Considering limited HR data adjusted for standard prognostic variables could be retrieved, future high-quality studies will be needed in evaluating the independent prognostic value of survivin expression in DLBCL.

Dallol A, Buhmeida A, Merdad A, et al.
Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast.
Tumour Biol. 2015; 36(12):9677-83 [PubMed] Related Publications
Invasive ductal carcinoma of the breast is the most common cancer affecting women worldwide. The marked heterogeneity of breast cancer is matched only with the heterogeneity in its associated or causative factors. Breast cancer in Saudi Arabia is apparently an early onset with many of the affected females diagnosed before they reach the age of 50 years. One possible rationale underlying this observation is that consanguinity, which is widely spread in the Saudi community, is causing the accumulation of yet undetermined cancer susceptibility mutations. Another factor could be the accumulation of epigenetic aberrations caused by the shift toward a Western-like lifestyle in the past two decades. In order to shed some light into the molecular mechanisms underlying breast cancer in the Saudi community, we identified KLOTHO (KL) as a tumor-specific methylated gene using genome-wide methylation analysis of primary breast tumors utilizing the MBD-seq approach. KL methylation was frequent as it was detected in 55.3 % of breast cancer cases from Saudi Arabia (n = 179) using MethyLight assay. Furthermore, KL is downregulated in breast tumors with its expression induced following treatment with 5-azacytidine. The involvement of KL in breast cancer led us to investigate its relationship in the context of breast cancer, with one of the protagonists of its function, fibroblast growth factor receptor 4 (FGFR4). Overexpression of FGFR4 in breast cancer is frequent in our cohort and this overexpression is associated with poor overall survival. Interestingly, FGFR4 expression is higher in the absence of KL methylation and lower when KL is methylated and presumably silenced, which is suggestive of an intricate relationship between the two factors. In conclusion, our findings further implicate "metabolic" genes or pathways in breast cancer that are disrupted by epigenetic mechanisms and could provide new avenues for understanding this disease in a new context.

Skoulidis F, Byers LA, Diao L, et al.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Cancer Discov. 2015; 5(8):860-77 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
UNLABELLED: The molecular underpinnings that drive the heterogeneity of KRAS-mutant lung adenocarcinoma are poorly characterized. We performed an integrative analysis of genomic, transcriptomic, and proteomic data from early-stage and chemorefractory lung adenocarcinoma and identified three robust subsets of KRAS-mutant lung adenocarcinoma dominated, respectively, by co-occurring genetic events in STK11/LKB1 (the KL subgroup), TP53 (KP), and CDKN2A/B inactivation coupled with low expression of the NKX2-1 (TTF1) transcription factor (KC). We further revealed biologically and therapeutically relevant differences between the subgroups. KC tumors frequently exhibited mucinous histology and suppressed mTORC1 signaling. KL tumors had high rates of KEAP1 mutational inactivation and expressed lower levels of immune markers, including PD-L1. KP tumors demonstrated higher levels of somatic mutations, inflammatory markers, immune checkpoint effector molecules, and improved relapse-free survival. Differences in drug sensitivity patterns were also observed; notably, KL cells showed increased vulnerability to HSP90-inhibitor therapy. This work provides evidence that co-occurring genomic alterations identify subgroups of KRAS-mutant lung adenocarcinoma with distinct biology and therapeutic vulnerabilities.
SIGNIFICANCE: Co-occurring genetic alterations in STK11/LKB1, TP53, and CDKN2A/B-the latter coupled with low TTF1 expression-define three major subgroups of KRAS-mutant lung adenocarcinoma with distinct biology, patterns of immune-system engagement, and therapeutic vulnerabilities.

Manchanda R, Loggenberg K, Sanderson S, et al.
Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial.
J Natl Cancer Inst. 2015; 107(1):379 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)-based testing.
METHODS: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided.
RESULTS: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%.
CONCLUSION: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn't adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.

Huang X, Qian Y, Wu H, et al.
Aberrant expression of osteopontin and E-cadherin indicates radiation resistance and poor prognosis for patients with cervical carcinoma.
J Histochem Cytochem. 2015; 63(2):88-98 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Radiotherapy is the first-line treatment for all stages of cervical cancer, whether it is used for radical or palliative therapy. However, radioresistance of cervical cancer remains a major therapeutic problem. Consequently, we explored if E-cadherin (a marker of epithelial-mesenchymal transition) and osteopontin could predict radioresistance in patients with locally advanced cervical squamous cell carcinoma (LACSCC). Patients were retrospectively reviewed and 111 patients divided into two groups (radiation-resistant and radiation-sensitive groups) according to progression-free survival (PFS). In pretreated paraffin-embedded tissues, we evaluated E-cadherin and osteopontin expression using immunohistochemical staining. The percentage of patients with high osteopontin but low E-cadherin expression in the radiation-resistant group was significantly higher than those in the radiation-sensitive group (p<0.001). These patients also had a lower 5-year PFS rate (p<0.001). Our research suggests that high osteopontin but low E-cadherin expression can be considered as a negative, independent prognostic factor in patients with LACSCC ([Hazard ratios (95% CI) 6.766 (2.940, 15.572)], p<0.001).

Terai H, Soejima K, Yasuda H, et al.
Long‑term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR‑mutant PC9 lung cancer cell line.
Int J Oncol. 2015; 46(1):430-6 [PubMed] Related Publications
This study was designed to identify epigenetically regulated genes and to clarify the contribution of epige-netic alteration to acquired resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs). We established a gefitinib‑resistant lung cancer cell line, PC9, which was originally gefitinib‑sensitive, by serial long‑term exposure to gefitinib. RNA and DNA were collected from both gefitinib‑sensitive and ‑resistant PC9 cells, and comprehensive DNA methylation and mRNA expression analyses were performed using Infinium HumanMethylation27 Bead Arrays and Agilent SurePrint G3 Human Gene Expression 8x60K Array, respectively. DNA methylation was increased in 640 genes in gefitinib‑resistant cells compared to parental cells. Among them, we selected 29 candidate genes that presented a decrease in mRNA expression in resistant PC9. We further studied four of the selected genes (C10orf116, IGFBP3, KL, and S100P) and found that KL or S100P silencing by siRNA induced a decrease in gefitinib sensitivity compared to that in the negative control in PC9. In conclusion, KL and S100P could be potential targets to overcome resistance to EGFR‑TKIs.

de Groot JS, Pan X, Meeldijk J, et al.
Validation of DNA promoter hypermethylation biomarkers in breast cancer--a short report.
Cell Oncol (Dordr). 2014; 37(4):297-303 [PubMed] Related Publications
PURPOSE: DNA promoter hypermethylation of tumor suppressor genes is known to occur early in cancer development, including breast cancer. To improve early breast cancer detection, we aimed to investigate whether the identification of DNA promoter hypermethylation might be of added value.
METHODS: The methylation status of a panel of 19 candidate genes (AKR1B1, ALX1, ARHGEF7, FZD10, GHSR, GPX7, GREM1, GSTP1, HOXD1, KL, LHX2, MAL, MGMT, NDRG2, RASGRF2, SFRP1, SFRP2, TM6SF1 and TMEFF2) was determined in formalin-fixed paraffin-embedded normal breast and breast cancer tissue samples using gel-based methylation-specific PCR (MSP).
RESULTS: The promoters of the AKR1B1, ALX1, GHSR, GREM1, RASGRF2, SFRP2, TM6SF1 and TMEFF2 genes were found to be significantly differentially methylated in normal versus malignant breast tissues. Based on sensitivity, specificity and logistic regression analyses the best performing genes for detecting breast cancer were identified. Through multivariate analyses, we found that AKR1B1 and TM6SF1 could detect breast cancer with an area under the curve (AUC) of 0.986 in a receiver operating characteristic (ROC) assessment.
CONCLUSIONS: Based on our data, we conclude that AKR1B1 and TM6SF1 may serve as candidate methylation biomarkers for early breast cancer detection. Further studies are underway to evaluate the methylation status of these genes in body fluids, including nipple aspirates and blood.

Kim HJ, Lee J, Lee SY, et al.
The association between KL polymorphism and prostate cancer risk in Korean patients.
Mol Biol Rep. 2014; 41(11):7595-606 [PubMed] Related Publications
The Klotho (KL) gene is a classical "aging suppressor" gene. Although recent studies have shown that KL participates in the progression of several types of human cancers, the relationship between KL polymorphism and prostate cancer was unknown. The present study aimed to investigate the association between KL genetic polymorphisms and prostate cancer. Twenty-five common single nucleotide polymorphisms (SNPs) in KL gene (including KL gene polymorphism C1818T in exon 4) were assessed in 272 prostate cancer cases and 173 controls. Single-locus analyses were conducted using unconditional logistic regression. In addition, we did a haplotype analysis for the 25 KL SNPs tested. CC genotype of C1548T KL polymorphism had approximately twofold increased prostate cancer risk compared with the homozygous genotype TT and heterozygote CT (odds ratio 1.85 [95% CI, 1.09-3.12], P = 0.02). We also found that non-T allele carriers had significantly higher prostate cancer risk associated with the prostate cancer clinical characteristics (tumor stage or Gleason score). Our findings suggested that the C1548T polymorphism of KL gene is associated with the prostate cancer and may act as a risk factor for the development of prostate cancer.

Shahmoon S, Rubinfeld H, Wolf I, et al.
The aging suppressor klotho: a potential regulator of growth hormone secretion.
Am J Physiol Endocrinol Metab. 2014; 307(3):E326-34 [PubMed] Related Publications
Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice (kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.

Kim B, Kang S, Jeong G, et al.
Identification and comparison of aberrant key regulatory networks in breast, colon, liver, lung, and stomach cancers through methylome database analysis.
PLoS One. 2014; 9(5):e97818 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Aberrant methylation of specific CpG sites at the promoter is widely responsible for genesis and development of various cancer types. Even though the microarray-based methylome analyzing techniques have contributed to the elucidation of the methylation change at the genome-wide level, the identification of key methylation markers or top regulatory networks appearing common in highly incident cancers through comparison analysis is still limited. In this study, we in silico performed the genome-wide methylation analysis on each 10 sets of normal and cancer pairs of five tissues: breast, colon, liver, lung, and stomach. The methylation array covers 27,578 CpG sites, corresponding to 14,495 genes, and significantly hypermethylated or hypomethylated genes in the cancer were collected (FDR adjusted p-value <0.05; methylation difference >0.3). Analysis of the dataset confirmed the methylation of previously known methylation markers and further identified novel methylation markers, such as GPX2, CLDN15, and KL. Cluster analysis using the methylome dataset resulted in a diagram with a bipartite mode distinguishing cancer cells from normal cells regardless of tissue types. The analysis further revealed that breast cancer was closest with lung cancer, whereas it was farthest from colon cancer. Pathway analysis identified that either the "cancer" related network or the "cancer" related bio-function appeared as the highest confidence in all the five cancers, whereas each cancer type represents its tissue-specific gene sets. Our results contribute toward understanding the essential abnormal epigenetic pathways involved in carcinogenesis. Further, the novel methylation markers could be applied to establish markers for cancer prognosis.

Li XX, Huang LY, Peng JJ, et al.
Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway.
Int J Oncol. 2014; 45(2):611-8 [PubMed] Related Publications
Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers including colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus‑mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.

Vijayakurup V, Spatafora C, Tringali C, et al.
Phenethyl caffeate benzoxanthene lignan is a derivative of caffeic acid phenethyl ester that induces bystander autophagy in WiDr cells.
Mol Biol Rep. 2014; 41(1):85-94 [PubMed] Related Publications
We recently reported that Phenethyl caffeate benzoxanthene lignan (PCBL), a semisynthetic compound derived from Caffeic Acid Phenethyl Ester (CAPE), induces DNA damage and apoptosis in tumor cells. In this study, we further investigated whether PCBL induces autophagy in WiDr cells. We also analyzed the pathways regulating autophagy and the role of autophagy in PCBL-induced cell death. Our acridine orange staining and LC3 II expression results suggest that PCBL induces autophagosomes in WiDr cells. The levels of LC3 II expression we observed after co-treatment of PCBL with bafilomycin A1 and the reductions in p62 expression we observed after PCBL treatment in WiDr cells demonstrate increased autophagic flux, a reliable indicator of autophagic induction. The increased Beclin 1 expression in PCBL-treated cells and the incapacity of PCBL to induce LC3 II in 3-methyladenine (3-MA)-treated cells we observed suggests that PCBL-induced autophagy is class III PI3-kinase dependent. PCBL did not alter phosphorylation of the mTOR substrate p70 S6 kinase, indicating that PCBL-induced autophagy was not mTOR regulated. Two autophagy related proteins, Atg5 and Atg12, also remained uninduced during PCBL treatment. The increased caspase activity and expression levels of LC3 II and p62 we observed in response to PCBL treatment in primary glioma cells demonstrates that PCBL-induced apoptosis and autophagy were not cell line specific. Pharmacological inhibition of autophagy did not alter the antitumor efficacy of PCBL in WiDr cells. This attests to the bystander nature of PCBL-induced autophagy (in terms of cell death). In toto, these data suggest that PCBL induces a class III kinase dependent, but mTOR independent, bystander mode of autophagy in WiDr cells.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

Lim SA, Kim TJ, Lee JE, et al.
Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy.
Cancer Res. 2013; 73(8):2598-607 [PubMed] Related Publications
Adoptive natural killer (NK) cell therapy may offer an effective treatment regimen for cancer patients whose disease is refractory to conventional therapy. NK cells can kill a wide range of tumor cells by patterned recognition of target ligands. We hypothesized that tumor targets sensitive to NK lysis would drive vigorous expansion of NK cells from human peripheral blood mononuclear cells (PBMC). Here, we provide the basis for developing a novel ex vivo expansion process. By screening class I-negative or -mismatched tumor cell lines we identified a Jurkat T-lymphoblast subline termed KL-1, which was highly effective in specifically expanding NK cells. KL-1 addition to PBMC cultures achieved approximately 100-fold expansion of NK cells with nearly 90% purity, accompanied by reciprocal inhibition of T-cell growth. Marked elevations in expression of activation receptors, natural cytotoxicity receptors (NKp30, NKp44), and adhesion molecules (CD11a, ICAM-1) were associated with high tumor-lytic capacity, in both in vitro and in vivo models. KL-1-mediated expansion of NK cells was contact dependent and required interactions with CD16, the Fcγ receptor on NK cells, with ligands that are expressed on B cells. Indeed, B-cell depletion during culture abrogated selective NK cell expansion, while addition of EBV-transformed B cells further augmented NK expansion to approximately 740-fold. Together, our studies define a novel method for efficient activation of human NK cells that employs KL-1-lysed tumor cells and cocultured B cells, which drive a robust expansion of potent antitumor effector cells that will be useful for clinical evaluation.

Rinner B, Weinhaeusel A, Lohberger B, et al.
Chordoma characterization of significant changes of the DNA methylation pattern.
PLoS One. 2013; 8(3):e56609 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Chordomas are rare mesenchymal tumors occurring exclusively in the midline from clivus to sacrum. Early tumor detection is extremely important as these tumors are resistant to chemotherapy and irradiation. Despite continuous research efforts surgical excision remains the main treatment option. Because of the often challenging anatomic location early detection is important to enable complete tumor resection and to reduce the high incidence of local recurrences. The aim of this study was to explore whether DNA methylation, a well known epigenetic marker, may play a role in chordoma development and if hypermethylation of specific CpG islands may serve as potential biomarkers correlated with SNP analyses in chordoma. The study was performed on tumor samples from ten chordoma patients. We found significant genomic instability by Affymetrix 6.0. It was interesting to see that all chordomas showed a loss of 3q26.32 (PIK 3CA) and 3q27.3 (BCL6) thus underlining the potential importance of the PI3K pathway in chordoma development. By using the AITCpG360 methylation assay we elucidated 20 genes which were hyper/hypomethylated compared to normal blood. The most promising candidates were nine hyper/hypomethylated genes C3, XIST, TACSTD2, FMR1, HIC1, RARB, DLEC1, KL, and RASSF1. In summary, we have shown that chordomas are characterized by a significant genomic instability and furthermore we demonstrated a characteristic DNA methylation pattern. These findings add new insights into chordoma development, diagnosis and potential new treatment options.

Ohtsuki Y, Kuroda N, Yunoki S, et al.
Immunohistochemical analysis of invasive micropapillary carcinoma pattern in four cases of gastric cancer.
Med Mol Morphol. 2013; 46(2):114-21 [PubMed] Related Publications
Gastric cancer with the invasive micropapillary carcinoma (IMPC) pattern has been reported to be a variant with poor prognosis and rapid progression. To the best of our knowledge, only 4 cases of gastric cancer from Japan and 11 cases from Korea have been reported to contain the IMPC pattern. In the present study, 4 cases of gastric cancer containing the IMPC pattern from 2 Japanese men and 2 Japanese women are reported. The cancer tissues, including a recurrent lesion in 1 case and lymph node metastases in 2 other cases, were examined immunohistochemically to identify suitable markers for demonstrating the peculiar "inside out" pattern of IMPC and for analyzing HER2 expression. A characteristic IMPC pattern occupied more than 10% of each cancer tissue in these 4 cases. Lymphatic invasions were very often detected; in fact, lymph node metastases were detected in 3 out of 4 cases. The unique "inside out" pattern in IMPC was clearly revealed in all cases by staining with antibodies to both epithelial membrane antigen (EMA) and KL-6, but not with an antibody to CD10. HER2 was positive in 3 of 4 cases with the IMPC pattern, including cases with a recurrent lesion or lymph node metastases. Fluorescence in situ hybridization (FISH) analyses disclosed positive results in case 1, and case 3 including lymph node metastatic foci. Highest FISH titer was 6.8 in case 1, revealing marked amplification of HER-2 gene. Four cases of gastric cancer with the IMPC pattern were reported. EMA and KL-6, but not CD10, were particularly useful markers for visualizing the characteristic "inside out" pattern of the IMPC pattern in stomach cancers, similar to the markers for breast and urinary bladder cancers.

Feng S, Dakhova O, Creighton CJ, Ittmann M
Endocrine fibroblast growth factor FGF19 promotes prostate cancer progression.
Cancer Res. 2013; 73(8):2551-62 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Prostate cancer is the most common visceral malignancy and the second leading cause of cancer deaths in US men. There is broad evidence that fibroblast growth factor (FGF) receptors are important in prostate cancer initiation and progression, but the contribution of particular FGFs in this disease is not fully understood. The FGF family members FGF19, FGF21, and FGF23 comprise a distinct subfamily that circulate in serum and act in an endocrine manner. These endocrine FGFs require α-Klotho (KL) and/or β-Klotho (KLB), two related single-pass transmembrane proteins restricted in their tissue distribution, to act as coreceptors along with classic FGF receptors (FGFR) to mediate potent biologic activity. Here we show that FGF19 is expressed in primary and metastatic prostate cancer tissues, where it functions as an autocrine growth factor. Exogenous FGF19 promoted the growth, invasion, adhesion, and colony formation of prostate cancer cells at low ligand concentrations. FGF19 silencing in prostate cancer cells expressing autocrine FGF19 decreased invasion and proliferation in vitro and tumor growth in vivo. Consistent with these observations, KL and/or KLB were expressed in prostate cancer cells in vitro and in vivo, raising the possibility that additional endocrine FGFs may also exert biologic effects in prostate cancer. Our findings support the concept that therapies targeting FGFR signaling may have efficacy in prostate cancer and highlight FGF19 as a relevant endocrine FGF in this setting.

Xie B, Zhou J, Yuan L, et al.
Epigenetic silencing of Klotho expression correlates with poor prognosis of human hepatocellular carcinoma.
Hum Pathol. 2013; 44(5):795-801 [PubMed] Related Publications
Klotho is identified as a tumor suppressor in several tumors, but the expression of the Klotho gene (KL) and its regulative mechanism are not reported in hepatocellular carcinoma (HCC). The messenger RNA and protein levels of Klotho were measured in 64 HCC tumor tissues by real-time polymerase chain reaction and immunohistochemistry, respectively. The methylation of KL promoter DNA was examined by bisulfite-based polymerase chain reaction. The correlation of Klotho protein expression and methylation with survival of HCC was analyzed using Kaplan-Meier analysis. The interference of KL gene expression was conducted in HCC cells by DNA demethylating agent and/or histone deacetylase inhibitor. In HCC tissues, a significant loss of Klotho messenger RNA and protein expression was observed, which parallels the increased methylation in KL promoter DNA. Both Klotho expression and methylation correlated with the poor prognosis of HCC. Experiments with HCC cell lines showed that a combination of DNA demethylating agent and histone deacetylase inhibitor fully recovered Klotho expression and subsequently induced cell apoptosis. In conclusion, Klotho is a tumor suppressor in HCC. Both hypermethylation and acetylation are involved in the loss of Klotho expression in HCC cells. Both KL gene expression and its promoter DNA methylation are predictive factors for the poor prognosis of HCC. Our study also suggests that the Klotho gene could be a target for therapy of HCC.

Sakellariou A, Sanoudou D, Spyrou G
Combining multiple hypothesis testing and affinity propagation clustering leads to accurate, robust and sample size independent classification on gene expression data.
BMC Bioinformatics. 2012; 13:270 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: A feature selection method in microarray gene expression data should be independent of platform, disease and dataset size. Our hypothesis is that among the statistically significant ranked genes in a gene list, there should be clusters of genes that share similar biological functions related to the investigated disease. Thus, instead of keeping N top ranked genes, it would be more appropriate to define and keep a number of gene cluster exemplars.
RESULTS: We propose a hybrid FS method (mAP-KL), which combines multiple hypothesis testing and affinity propagation (AP)-clustering algorithm along with the Krzanowski & Lai cluster quality index, to select a small yet informative subset of genes. We applied mAP-KL on real microarray data, as well as on simulated data, and compared its performance against 13 other feature selection approaches. Across a variety of diseases and number of samples, mAP-KL presents competitive classification results, particularly in neuromuscular diseases, where its overall AUC score was 0.91. Furthermore, mAP-KL generates concise yet biologically relevant and informative N-gene expression signatures, which can serve as a valuable tool for diagnostic and prognostic purposes, as well as a source of potential disease biomarkers in a broad range of diseases.
CONCLUSIONS: mAP-KL is a data-driven and classifier-independent hybrid feature selection method, which applies to any disease classification problem based on microarray data, regardless of the available samples. Combining multiple hypothesis testing and AP leads to subsets of genes, which classify unknown samples from both, small and large patient cohorts with high accuracy.

Chen B, Ma X, Liu S, et al.
Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner.
Cancer Biol Ther. 2012; 13(12):1221-8 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Klotho (KL) is a transmembrane protein that can be shed, and act as a circulating hormone and modulate several signaling pathways. There also exists a splice variant of Klotho mRNA, which encodes a putative secreted protein (Klotho-S, KL-S) in both human and mouse. The potential anti-senescence gene Klotho has been recently found to participate in the progression of several different human cancers. In the current study, we undertook to study the expression and activity of Klotho in lung cancer cell line A549. Klotho expression was studied by using RT-PCR and western blotting. Effects of Klotho on cell growth and motility were assessed using MTT and scratch motility assay, and the apoptosis was assessed by TUNEL. Wnt signaling pathway activity was measured by western blotting. We established that the Klotho was endogenous expressed in A549 cells, but the expression level is lower compared with normal lung tissues. The overexpression of KL or KL-S could inhibit the cell proliferation, motility, and induce apoptosis in a dose-dependent manner. Also, we report KL could inhibit activation of Wnt -TCF/β-catenin signaling pathway, and it is involved in KL-induced growth inhibition. These studies indicate Klotho works as a potential tumor suppressor in lung cancer, and suggest that the Klotho tumor suppressive activities could be mediated through its KL-S isoform. These results suggest the use of Klotho or KL-S as potential strategy for the development of novel therapeutic interventions for lung cancers.

Saini V, Hose CD, Monks A, et al.
Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma.
PLoS One. 2012; 7(8):e41401 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma.

Jeschke J, Van Neste L, Glöckner SC, et al.
Biomarkers for detection and prognosis of breast cancer identified by a functional hypermethylome screen.
Epigenetics. 2012; 7(7):701-9 [PubMed] Related Publications
Breast cancer (BC) is a disease with diverse tumor heterogeneity, which challenges conventional approaches to develop biomarkers for early detection and prognosis. To identify effective biomarkers, we performed a genome-wide screen for functional methylation changes in BC, i.e., genes silenced by promoter hypermethylation, using a functionally proven gene expression approach. A subset of candidate hypermethylated genes were validated in primary BCs and tested as markers for detection and prognosis prediction of BC. We identified 33 cancer specific methylated genes and, among these, two categories of genes: (1) highly frequent methylated genes that detect early stages of BC. Within that category, we have identified the combination of NDRG2 and HOXD1 as the most sensitive (94%) and specific (90%) gene combination for detection of BC; (2) genes that show stage dependent methylation frequency pattern, which are candidates to help delineate BC prognostic signatures. For this category, we found that methylation of CDO1, CKM, CRIP1, KL and TAC1 correlated with clinical prognostic variables and was a significant prognosticator for poor overall survival in BC patients. CKM [Hazard ratio (HR) = 2.68] and TAC1 (HR = 7.73) were the strongest single markers and the combination of both (TAC1 and CKM) was associated with poor overall survival independent of age and stage in our training (HR = 1.92) and validation cohort (HR = 2.87). Our study demonstrates an efficient method to utilize functional methylation changes in BC for the development of effective biomarkers for detection and prognosis prediction of BC.

Laitman Y, Kuchenbaecker KB, Rantala J, et al.
The KL-VS sequence variant of Klotho and cancer risk in BRCA1 and BRCA2 mutation carriers.
Breast Cancer Res Treat. 2012; 132(3):1119-26 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Klotho (KL) is a putative tumor suppressor gene in breast and pancreatic cancers located at chromosome 13q12. A functional sequence variant of Klotho (KL-VS) was previously reported to modify breast cancer risk in Jewish BRCA1 mutation carriers. The effect of this variant on breast and ovarian cancer risks in non-Jewish BRCA1/BRCA2 mutation carriers has not been reported. The KL-VS variant was genotyped in women of European ancestry carrying a BRCA mutation: 5,741 BRCA1 mutation carriers (2,997 with breast cancer, 705 with ovarian cancer, and 2,039 cancer free women) and 3,339 BRCA2 mutation carriers (1,846 with breast cancer, 207 with ovarian cancer, and 1,286 cancer free women) from 16 centers. Genotyping was accomplished using TaqMan(®) allelic discrimination or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed within a retrospective cohort approach, stratified by country of origin and Ashkenazi Jewish origin. The per-allele hazard ratio (HR) for breast cancer was 1.02 (95% CI 0.93-1.12, P = 0.66) for BRCA1 mutation carriers and 0.92 (95% CI 0.82-1.04, P = 0.17) for BRCA2 mutation carriers. Results remained unaltered when analysis excluded prevalent breast cancer cases. Similarly, the per-allele HR for ovarian cancer was 1.01 (95% CI 0.84-1.20, P = 0.95) for BRCA1 mutation carriers and 0.9 (95% CI 0.66-1.22, P = 0.45) for BRCA2 mutation carriers. The risk did not change when carriers of the 6174delT mutation were excluded. There was a lack of association of the KL-VS Klotho variant with either breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Shu M, Zhou Y, Zhu W, et al.
MicroRNA 335 is required for differentiation of malignant glioma cells induced by activation of cAMP/protein kinase A pathway.
Mol Pharmacol. 2012; 81(3):292-8 [PubMed] Related Publications
Glioma is the most common malignant cancer affecting the central nerve system, with dismal prognosis. Differentiation-inducing therapy is a novel strategy that has been preliminarily proved effective against malignant glioma. We have reported previously that activation of cAMP/protein kinase A (PKA) pathway is capable of inducing glioma cell differentiation, characterized by astrocyte-like shape and dramatic induction of astrocyte biomarker glial fibrillary acidic protein (GFAP). However, little progress has been made on molecular mechanisms related. Here we demonstrate that microRNA 335 (miR-335) is responsible for the glioma cell differentiation stimulated by activation of cAMP/PKA pathway. In the cAMP elevator cholera toxin-induced differentiation model of rat C6 glioma cells, miR-335 was significantly up-regulated, which was mimicked by other typical cAMP/PKA pathway activators (e.g., forskolin, dibutyryl-cAMP) and abolished by PKA-specific inhibitor (9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i] [1,6]benzodiazocine-10-carboxylic acid, hexyl ester (KT5720). In an assay measuring gain and loss of miR-335 function, exogenetic miR-335 resulted in induction of GFAP, whereas miR-335 specific inhibitor antagomir-335 violently blocked cholera toxin-induced GFAP up-regulation. It is noteworthy that in human U87-MG glioma cells and human primary culture glioma cells, miR-335 also mediated cholera toxin-induced differentiation. Taken together, our findings suggest that miR-335 is potently required for differentiation of malignant glioma cells induced by cAMP/PKA pathway activation, and a single microRNA may act as an important fate determinant to control the differentiation status of malignant gliomas, which has provided a new insight into differentiation-inducing therapy against malignant gliomas.

Seko A, Ohkura T, Ideo H, Yamashita K
Novel O-linked glycans containing 6'-sulfo-Gal/GalNAc of MUC1 secreted from human breast cancer YMB-S cells: possible carbohydrate epitopes of KL-6(MUC1) monoclonal antibody.
Glycobiology. 2012; 22(2):181-95 [PubMed] Related Publications
Human serum Krebs von den Lugen-6 (KL-6) antigen is a MUC1 glycoprotein (KL-6/MUC1) recognized by anti-KL-6 monoclonal antibody (KL-6/mAb) and has been utilized as a diagnostic marker for interstitial pneumonia. KL-6/mAb is thought to recognize the specific glycopeptides sequence of MUC1, but the precise glycan structure of the epitope is unclear. In this study, we determined the carbohydrate structures of KL-6/MUC1 to search the carbohydrate epitopes for KL-6/mAb. KL-6/MUC1 was purified from the culture medium of human breast cancer YMB-S cells by KL-6/mAb-affinity chromatography; the O-linked glycan structures were determined in combination with paper electrophoresis, several lectin column chromatographies, sialidase digestion and methanolysis. KL-6/MUC1 contained core 1 and extended core 1 glycans modified with one or two sialic acid/sulfate residues. Based on these structures, several synthetic glycans binding to anti-KL-6/mAb were compared with one another by surface plasmon resonance. Sequentially, related radiolabeled oligosaccharides were enzymatically synthesized and analyzed for binding to a KL-6/mAb-conjugated affinity column. 3'-sialylated, 6'-sulfated LNnT [Neu5Acα2-3(SO(3)(-)-6)Galβ1-4GlcNAcβ1-3Galβ1-4Glc], 3'-sialylated, 6-sulfated core 1 [Neu5Acα2-3Galβ1-3(SO(3)(-)-6)GalNAc] and disulfated core 1 SO(3)(-)-3Galβ1-3(SO(3)(-)-6)GalNAc exhibited substantial affinity for KL-6/mAb, and 3'-sulfated core 1 derivatives [SO(3)(-)-3Galβ1-3(±Neu5Acα2-6)GalNAc] and 3'-sialylated core 1 weakly interacted with KL-6/mAb. These results indicated that the possible carbohydrate epitopes of KL-6/mAb involve not only 3'-sialylated core 1 but also novel core 1 and extended core 1 with sulfate and sialic acid residues. Epitope expressing changes with suppression or over-expression of the Gal6ST (Gal 6-O-sulfotransferase) gene, suggesting that Gal6ST is involved in the biosynthesis of the unique epitopes of KL-6/mAb.

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