Gene Summary

Gene:S100A6; S100 calcium binding protein A6
Aliases: 2A9, PRA, 5B10, CABP, CACY, S10A6
Summary:The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in stimulation of Ca2+-dependent insulin release, stimulation of prolactin secretion, and exocytosis. Chromosomal rearrangements and altered expression of this gene have been implicated in melanoma. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:protein S100-A6
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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

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

Latest Publications: S100A6 (cancer-related)

Hung CY, Lee CH, Chiou HL, et al.
Praeruptorin-B Inhibits 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Invasion by Targeting AKT/NF-κB via Matrix Metalloproteinase-2/-9 Expression in Human Cervical Cancer Cells.
Cell Physiol Biochem. 2019; 52(6):1255-1266 [PubMed] Related Publications
BACKGROUND/AIMS: Praeruptorins, a seselin-type coumarin, possess anti-inflammatory and antitumor promoting properties. However, molecular mechanisms through which Praeruptorin-B (Pra-B) exerts an antimetastatic effect on cervical cancer cells remain unclear.
METHODS: Cell viability was examined using the MTT assay, whereas cell migration and invasion were examined using the Boyden chamber assay. Western blotting and RT-PCR were performed to investigate the inhibitory effect of Pra-B on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-2/-9 (MMP-2/-9) expression in HeLa cells. The findings of the luciferase assay confirmed the inhibitory effect of Pra-B on TPA-induced transcriptional activity of MMP2/-9 in HeLa cells.
RESULTS: Pra-B inhibited TPA-induced metastatic ability of human cervical cancer cells without any significant toxicity. Pra-B suppressed TPA-induced mRNA and protein expression and transcriptional activity of MMP-2/-9 in HeLa cells. Furthermore, Pra-B inhibited AKT phosphorylation but did not affect the MAPK pathway. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 (a PI3K inhibitor) reduced cell invasion and MMP-2/-9 expression and transcriptional activity. In addition, Pra-B attenuated TPA-induced nuclear translocation of NF-κB-p65/-p50, which reduced Ikk-α phosphorylation in HeLa cells. Cotreatment of HeLa cells with TPA plus Pra-B or LY294002 reduced NF-κB nuclear translocation.
CONCLUSION: These results suggested that Pra-B-mediated inhibition of TPA-induced cell metastasis involved the suppression of p-AKT/NF-κB via MMP-2/-9 expression in HeLa cells. Pra-B can be a potential antimetastatic agent against cervical cancer.

Bai Y, Li LD, Li J, Lu X
Prognostic values of S100 family members in ovarian cancer patients.
BMC Cancer. 2018; 18(1):1256 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Exhibiting high consistence in sequence and structure, S100 family members are interchangeable in function and they show a wide spectrum of biological processes, including proliferation, apoptosis, migration, inflammation and differentiation and the like. While the prognostic value of each individual S100 in ovarian cancer is still elusive. In current study, we investigated the prognostic value of S100 family members in the ovarian cancer.
METHODS: We used the Kaplan Meier plotter (KM plotter) database, in which updated gene expression data and survival information are from 1657 ovarian cancer patients, to assess the relevance of individual S100 family mRNA expression to overall survival in various ovarian cancer subtypes and different clinicopathological features.
RESULTS: It was found that high expression of S100A2 (HR = 1.18, 95%CI: 1.04-1.34, P = 0.012), S100A7A (HR = 1.3, 95%CI: 1.04-1.63, P = 0.02),S100A10 (HR = 1.2, 95%CI: 1.05-1.38, P = 0.0087),and S100A16 (HR = 1.23, 95%CI: 1-1.51, P = 0.052) were significantly correlated with worse OS in all ovarian cancer patients, while the expression of S100A1 (HR = 0.87, 95%CI: 0.77-0.99, P = 0.039), S100A3 (HR = 0.83, 95%CI: 0.71-0.96, P = 0.0011), S100A5 (HR = 0.84, 95%CI: 0.73-0.97, P = 0.017), S100A6 (HR = 0.84, 95%CI: 0.72-0.98, P = 0.024), S100A13 (HR = 0.85, 95%CI:0.75-0.97, P = 0.014) and S100G (HR = 0.86, 95%CI: 0.74-0.99, P = 0.041) were associated with better prognosis. Furthermore, we assessed the prognostic value of S100 expression in different subtypes and the clinicopathological features, including pathological grades, clinical stages and TP53 mutation status, of ovarian cancer patients.
CONCLUSION: Comprehensive understanding of the S100 family members may have guiding significance for the diagnosis and outcome of ovarian cancer patients.

Khoontawad J, Intuyod K, Rucksaken R, et al.
Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer.
PLoS One. 2018; 13(11):e0207405 [PubMed] Free Access to Full Article Related Publications
Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti-inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA-harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-κB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer.

Carlini MJ, Recouvreux MS, Simian M, Nagai MA
Gene expression profile and cancer-associated pathways linked to progesterone receptor isoform a (PRA) predominance in transgenic mouse mammary glands.
BMC Cancer. 2018; 18(1):682 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Progesterone receptor (PR) is expressed from a single gene as two isoforms, PRA and PRB. In normal breast human tissue, PRA and PRB are expressed in equimolar ratios, but isoform ratio is altered during malignant progression, usually leading to high PRA:PRB ratios. We took advantage of a transgenic mouse model where PRA isoform is predominant (PRA transgenics) and identified the key transcriptional events and associated pathways underlying the preneoplastic phenotype in mammary glands of PRA transgenics as compared with normal wild-type littermates.
METHODS: The transcriptomic profiles of PRA transgenics and wild-type mammary glands were generated using microarray technology. We identified differentially expressed genes and analyzed clustering, gene ontology (GO), gene set enrichment analysis (GSEA), and pathway profiles. We also performed comparisons with publicly available gene expression data sets of human breast cancer.
RESULTS: We identified a large number of differentially expressed genes which were mainly associated with metabolic pathways for the PRA transgenics phenotype while inflammation- related pathways were negatively correlated. Further, we determined a significant overlap of the pathways characterizing PRA transgenics and those in breast cancer subtypes Luminal A and Luminal B and identified novel putative biomarkers, such as PDHB and LAMB3.
CONCLUSION: The transcriptional targets identified in this study should facilitate the formulation or refinement of useful molecular descriptors for diagnosis, prognosis, and therapy of breast cancer.

Chen, Luo L, Liang C
Aberrant S100A16 expression might be an independent prognostic indicator of unfavorable survival in non-small cell lung adenocarcinoma.
PLoS One. 2018; 13(5):e0197402 [PubMed] Free Access to Full Article Related Publications
S100A16 is a conserved member of the S100 protein family in mammals. Its upregulation was observed in many tumors and is related to malignant transformation. In this study, we explored the independent prognostic value of S100A16 in terms of overall survival (OS) and recurrence-free survival (RFS) by performing a retrospective study, using data in The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD). Besides, by using deep sequencing data in TCGA-LUAD, we also explored the association between S100A16 expression and its DNA methylation and copy number alterations (CNAs). Results showed that the primary LUAD tissues (N = 514) had significantly elevated S100A16 expression compared with the normal lung tissues (N = 59). Based on OS data of 502 primary LUAD cases, we found that high S100A16 expression was correlated with inferior OS. The following univariate and multivariate analysis confirmed that increased S100A16 expression was an independent prognostic indicator of unfavorable OS (HR: 1.197, 95%CI: 1.050-1.364, p = 0.007) and RFS (HR: 1.206, 95%CI: 1.045-1.393, p = 0.011). By examining the DNA methylation data in TCGA-LUAD, we found that some S100A16 DNA CpG sites were generally hypermethylated in normal tissues, but not in LUAD tissues. Regression analysis identified a moderately negative correlation between S100A16 expression and its DNA methylation. In comparison, although DNA amplification (+1/+2) was frequent (378/511, 74%) in LUAD patients, it was not associated with increased S100A16 expression. Based on findings above, we infer that aberrant S100A16 expression might be modulated by its DNA hypomethylation and serves as an independent prognostic indicator of unfavorable OS and RFS in LUAD.

Feng S, Zhou Q, Yang B, et al.
The effect of S100A6 on nuclear translocation of CacyBP/SIP in colon cancer cells.
PLoS One. 2018; 13(3):e0192208 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Calcyclin Binding Protein/(Siah-1 interacting protein) (CacyBP/SIP) acts as an oncogene in colorectal cancer. The nuclear accumulation of CacyBP/SIP has been linked to the proliferation of cancer cells. It has been reported that intracellular Ca2+ induces the nuclear translocation of CacyBP/SIP. However, the molecular mechanism of CacyBP/SIP nuclear translocation has yet to be elucidated. The purpose of this study was to test whether the Ca2+-dependent binding partner S100 protein is involved in CacyBP/SIP nuclear translocation in colon cancer SW480 cells.
METHODS: The subcellular localization of endogenous CacyBP/SIP was observed following the stimulation of ionomycin or BAPTA/AM by immunofluorescence staining in SW480 cells. S100A6 small interfering RNAs (siRNA) were transfected into SW480 cells. Immunoprecipitation assays detected whether S100 protein is relevant to the nuclear translocation of CacyBP/SIP in response to changes in [Ca2+]i.
RESULTS: We observed that endogenous CacyBP/SIP is translocated from the cytosol to the nucleus following the elevation of [Ca2+]i by ionomycin in SW480 cells. Co-immunoprecipitation experiments showed that the interaction between S100A6 and CacyBP/SIP was increased simultaneously with elevated Ca2+. Knockdown of S100A6 abolished the Ca2+ effect on the subcellular translocation of CacyBP/SIP.
CONCLUSION: Thus, we demonstrated that S100A6 is required for the Ca2+-dependent nuclear translocation of CacyBP/SIP in colon cancer SW480 cells.

Yazdani S, Kasajima A, Onodera Y, et al.
Progesterone arrested cell cycle progression through progesterone receptor isoform A in pancreatic neuroendocrine neoplasm.
J Steroid Biochem Mol Biol. 2018; 178:243-253 [PubMed] Related Publications
In pancreatic neuroendocrine neoplasms (Pan-NEN) progesterone signaling has been shown to have both inhibitory and stimulatory effects on cell proliferation. The ability of progesterone to inhibit tumor proliferation is of particular interest and is suggested to be mediated through the less abundantly expressed progesterone receptor (PR) isoform A (PRA). To date the mechanistic processes underlying this inhibition of proliferation remain unclear. To examine the mechanism of PRA actions, the human Pan-NEN cell line QGP-1, that endogenously expresses PR isoform B (PRB) without PRA, was transfected with PRA. PRA transfection suppressed the majority of cell cycle related genes increased by progesterone including cyclin A2 (CCNA2), cyclin B1 (CCNB1), cyclin-dependent kinase 1 (CDK1) and cyclin-dependent kinase 2 (CDK2). Importantly, following progesterone administration cell cycle distribution was shifted to S and G2/M phases in the naïve cell line but in PRA-transfected cells, this effect was suppressed. To see if these mechanistic insights were confirmed in patient samples PRA, PRB, CCNA2, CCNB, CDK1 and CDK2 immunoreactivities were assessed in Pan-NEN cases. Higher levels of cell cycle markers were associated with higher WHO grade tumors and correlations between the markers suggested formation of cyclin/CDK activated complexes in S and G2/M phases. PRA expression was associated with inverse correlation of all cell cycle markers. Collectively, these results indicate that progesterone signals through PRA negatively regulates cell cycle progression through suppressing S and G2/M phases and downregulation of cell cycle phases specific cyclins/CDKs.

Kim CW, Oh ET, Kim JM, et al.
Hypoxia-induced microRNA-590-5p promotes colorectal cancer progression by modulating matrix metalloproteinase activity.
Cancer Lett. 2018; 416:31-41 [PubMed] Related Publications
Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. MicroRNAs (miRNAs) are small non-coding RNA that have emerged as key players involved in cancer development and progression. Hypoxia alters a set of hypoxia-mediated miRNAs expression during tumor development and it may function as oncogenes or tumor-suppressors. However, the roles and molecular mechanisms of hypoxia-regulatory miRNAs in colorectal cancer (CRC) progression remain poorly understood. Here we firstly identified miR-590-5p as hypoxia-sensitive miRNAs which was upregulated in colon cancer cells under hypoxia. Hypoxia-induced miR-590-5p suppressed the expression of RECK, in turn, promoting cell invasiveness and migratory abilities via activation of matrix metalloproteinases (MMPs) and filopodia protrusion in vitro. Inhibition of miR-590-5p suppressed tumor growth and metastasis in mouse xenograft and CRC liver metastasis models via inhibition of MMPs activity. Clinical analysis revealed higher miR-590-5p expression in CRC, compared to normal specimens. Furthermore, miR-590-5p expression was significantly increased in liver metastasis as compared to their matched primary CRC. Taken together, our findings provide the first evidence that miR-590-5p may have potential as a therapeutic target for CRC patients with metastasis.

Zheng S, Shen H, Jia Q, et al.
S100A6 promotes proliferation of intrahepatic cholangiocarcinoma cells via the activation of the p38/MAPK pathway.
Future Oncol. 2017; 13(23):2053-2063 [PubMed] Related Publications
AIM: We explored the expression of S100A6 and its role in intrahepatic cholangiocarcinoma (ICC).
METHODS: The expression of S100A6 in ICC samples was detected by immunohistochemistry. In vitro experiments, we silenced and overexpressed S100A6 to investigate its role in cell functions.
RESULTS: The expression of S100A6 was markedly increased in ICC tissues and cell lines. S100A6 overexpression was an independent risk factor for patients' survival. Silencing S100A6 resulted in a suppression of proliferation and p38/MAPK activity, while overexpressing S100A6 caused a promotion of proliferation and p38/MAPK.
DISCUSSION:  S100A6 participated in the proliferation of ICC cells and correlated with a more aggressive behavior of ICC. Conclusion: S100A6 may serve as a novel prognostic marker and a potential therapeutic target for ICC patients.

Tamai H, Yamaguchi H, Miyake K, et al.
Amlexanox Downregulates S100A6 to Sensitize
Cancer Res. 2017; 77(16):4426-4433 [PubMed] Related Publications
Acute lymphoblastic leukemias (ALL) positive for

Huang X, Li Y, Song J, Berry DA
A Bayesian Simulation Model for Breast Cancer Screening, Incidence, Treatment, and Mortality.
Med Decis Making. 2018; 38(1_suppl):78S-88S [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The important but complicated research questions regarding the optimization of mammography screening for the detection of breast cancer are unable to be answered through any single trial or a simple meta-analysis of related trials. The Cancer Intervention and Surveillance Network (CISNET) breast groups provide answers using complex statistical models to simulate population dynamics. Among them, the MD Anderson Cancer Center (Model M) takes a unique approach by not making any assumptions on the natural history of breast cancer, such as the distribution of the indolent time before detection, but simulating only the observable part of a woman's disease and life.
METHODS: The simulations start with 4 million women in the age distribution found in the year 1975, and follow them over several years. Input parameters are used to describe their breast cancer incidence rates, treatment efficacy, and survival. With these parameters, each woman's history of breast cancer diagnosis, treatment, and survival are generated and recorded each year. Research questions can then be answered by comparing the outcomes of interest, such as mortality rates, quality-adjusted life years, number of false positives, differences between hypothetical scenarios, such as different combinations of screening and treatment strategies. We use our model to estimate the relative contributions of screening and treatments on the mortality reduction in the United States, for both overall and different molecular (ER, HER2) subtypes of breast cancer.
RESULTS: We estimate and compare the benefits (life-years gained) and harm (false-positives, over-diagnoses) of mammography screening strategies with different frequencies (annual, biennial, triennial, mixed) and different starting (40 and 50 years) and end ages (70 and 80 years).
CONCLUSIONS: We will extend our model in future studies to account for local, regional, and distant disease recurrences.

Donato R, Sorci G, Giambanco I
S100A6 protein: functional roles.
Cell Mol Life Sci. 2017; 74(15):2749-2760 [PubMed] Related Publications
S100A6 protein belongs to the A group of the S100 protein family of Ca

Rojas PA, May M, Sequeira GR, et al.
Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness.
J Natl Cancer Inst. 2017; 109(7) [PubMed] Free Access to Full Article Related Publications
Background: Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics.
Methods: We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided.
Results: One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P <  .001). PRB-H tumors showed increased tumor size ( P <  .001), Ki-67 levels ( P <  .001), human epidermal growth factor receptor 2 expression ( P =  .04), high grades ( P =  .03), and decreased total PR ( P =  .004) compared with PRA-H tumors. MUC-2 ( P <  .001) and KRT6A ( P =  .02) were also overexpressed in PRB-H tumors.
Conclusion: The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.

Florea AM, Varghese E, McCallum JE, et al.
Calcium-regulatory proteins as modulators of chemotherapy in human neuroblastoma.
Oncotarget. 2017; 8(14):22876-22893 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma (NB) is a pediatric cancer treated with poly-chemotherapy including platinum complexes (e.g. cisplatin (CDDP), carboplatin), DNA alkylating agents, and topoisomerase I inhibitors (e.g. topotecan (TOPO)). Despite aggressive treatment, NB may become resistant to chemotherapy. We investigated whether CDDP and TOPO treatment of NB cells interacts with the expression and function of proteins involved in regulating calcium signaling. Human neuroblastoma cell lines SH-SY5Y, IMR-32 and NLF were used to investigate the effects of CDDP and TOPO on cell viability, apoptosis, calcium homeostasis, and expression of selected proteins regulating intracellular calcium concentration ([Ca2+]i). In addition, the impact of pharmacological inhibition of [Ca2+]i-regulating proteins on neuroblastoma cell survival was studied. Treatment of neuroblastoma cells with increasing concentrations of CDDP (0.1-10 μM) or TOPO (0.1 nM-1 μM) induced cytotoxicity and increased apoptosis in a concentration- and time-dependent manner. Both drugs increased [Ca2+]i over time. Treatment with CDDP or TOPO also modified mRNA expression of selected genes encoding [Ca2+]i-regulating proteins. Differentially regulated genes included S100A6, ITPR1, ITPR3, RYR1 and RYR3. With FACS and confocal laser scanning microscopy experiments we validated their differential expression at the protein level. Importantly, treatment of neuroblastoma cells with pharmacological modulators of [Ca2+]i-regulating proteins in combination with CDDP or TOPO increased cytotoxicity. Thus, our results confirm an important role of calcium signaling in the response of neuroblastoma cells to chemotherapy and suggest [Ca2+]i modulation as a promising strategy for adjunctive treatment.

Zhang S, Wang Z, Liu W, et al.
Distinct prognostic values of S100 mRNA expression in breast cancer.
Sci Rep. 2017; 7:39786 [PubMed] Free Access to Full Article Related Publications
S100 family genes encode low molecular weight, acidic-Ca

Li A, Shi D, Xu B, et al.
S100A6 promotes cell proliferation in human nasopharyngeal carcinoma via the p38/MAPK signaling pathway.
Mol Carcinog. 2017; 56(3):972-984 [PubMed] Related Publications
An elevated level of S100A6 is associated with poor outcomes of many tumor types, but, how S100A6 contributes to nasopharyngeal carcinoma (NPC) progression remains unknown. Here, we investigated the expression and prognostic significance of S100A6 in NPC and explored the molecular mechanisms under-lying the role of S100A6 in NPC development. The results showed that S100A6 was markedly up-regulated in NPC tissues and cell lines compared to paired peritumoral normal tissues and a normal nasopharyngeal epithelial cell line, respectively. In tissues from 92 NPC patients, high S100A6 expression was associated with advanced N stage, locoregional failure and disease progression and was predictive of poor locoregional recurrence-free survival (LRRFS, P = 0.001) and progression-free survival (PFS, P = 0.001). Multivariate analysis showed that S100A6 is an independent prognostic factor for LRRFS and PFS. Silencing S100A6 using siRNA or shRNA significantly suppressed NPC cell proliferation, colony formation and p38/mitogen-activated protein kinase (MAPK) activity in vitro and inhibited tumor growth in a xenograft mouse model of NPC. In contrast, overexpressing S100A6 via plasmid transfection resulted in increased NPC cell proliferation and p38/MAPK activation. S100A6-induced proliferation was abolished by a p38 inhibitor. In summary, S100A6 may be a new prognostic marker of NPC and may promote NPC development via the activation of p38/MAPK signaling pathways. These findings suggest S100A6/p38/MAPK signaling as a potential therapeutic target for NPC. © 2016 Wiley Periodicals, Inc.

Loghavi S, Bueso-Ramos CE, Kanagal-Shamanna R, et al.
Myeloproliferative Neoplasms With Calreticulin Mutations Exhibit Distinctive Morphologic Features.
Am J Clin Pathol. 2016; 145(3):418-27 [PubMed] Related Publications
OBJECTIVES: Calreticulin (CALR) mutations are present in 50% to 85% of JAK2/MPL wild-type (wt) myeloproliferative neoplasms (MPNs). The histopathologic features of CALR-mutated MPNs are unknown.
METHODS: We identified 71 patients with essential thrombocythemia (ET), primary myelofibrosis (PMF), and post-essential thrombocythemia myelofibrosis (post-ET MF) with available CALR status. CALR was assessed using capillary electrophoresis followed by Sanger sequencing confirmation. CALR status was correlated with histopathologic features.
RESULTS: The megakaryocytes of CALR-mutated PMF more often were hyperchromatic (20/21) compared with CALR-wt cases (10/14) (P = .05). CALR-mutated ET showed more megakaryocytic clustering (7/7) compared with CALR-wt cases (5/9) (P = 03). Megakaryocytes of CALR-mutated post-ET MF (8/8) had a predominance of convoluted nuclei compared with CALR-wt cases (2/4) (P = .03). CALR mutations were more frequent in post-ET MF compared with ET (P = .04).
CONCLUSIONS: CALR-mutated MPNs have a higher frequency of megakaryocytic aberrancies compared with CALR-wt cases. Patients with CALR-mutated ET appear to be more likely to develop myelofibrosis compared with patients with wt CALRUpon completion of this activity you will be able to: describe morphologic features that are associated with CALR-mutated myeloproliferative neoplasms.examine cases of essential thrombocythemia and primary myelofibrosis and predict which cases are more likely to be CALR-mutated based on histopathologic features.initiate CALR mutation testing for cases likely to have mutations.  The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™ per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Exam is located at www.ascp.org/ajcpcme.

Kim H, Hong SH, Lee SA, et al.
Development of Fok-I based nested polymerase chain reaction-restriction fragment length polymorphism analysis for detection of hepatitis B virus X region V5M mutation.
World J Gastroenterol. 2015; 21(47):13360-7 [PubMed] Free Access to Full Article Related Publications
AIM: To develop a Fok-I nested polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis (PRA) method for the detection of hepatitis B virus X region (HBx) V5M mutation.
METHODS: Nested PCR was applied into DNAs from 198 chronic patients at 2 different stages [121 patients with hepatocellular carcinoma (HCC) and 77 carrier patients]. To identify V5M mutants, digestion of nested PCR amplicons by the restriction enzyme Fok-I (GGA TGN9↓) was done. For size comparison, the enzyme-treated products were analyzed by electrophoresis on 2.5% agarose gels, stained with ethidium bromide, and visualized on a UV transilluminator.
RESULTS: The assay enabled the identification of 69 patients (sensitivity of 34.8%; 46 HCC patients and 23 carrier patients). Our data also showed that V5M prevalence in HCC patients was significantly higher than in carrier patients (47.8%, 22/46 patients vs 0%, 0/23 patients, P < 0.001), suggesting that HBxAg V5M mutation may play a pivotal role in HCC generation in chronic patients with genotype C infections.
CONCLUSION: The Fok-I nested PRA developed in this study is a reliable and cost-effective method to detect HBxAg V5M mutation in chronic patients with genotype C2 infection.

Ismail MF, El Boghdady NA, Shabayek MI, et al.
Evaluation and screening of mRNA S100A genes as serological biomarkers in different stages of bladder cancer in Egypt.
Tumour Biol. 2016; 37(4):4621-31 [PubMed] Related Publications
Calcium-binding proteins S100A are multifunctional proteins that show altered expression in various diseases and cancers. This study aimed at validating an easier and less time-consuming technique to evaluate the value of combined use of messenger RNA (mRNA) S100A genes in comparison and combination with voided urine cytology in detection of bladder cancer patients. Blood and urine specimens were collected from patients (n = 120) with histologically confirmed bladder carcinoma who are classified according to bladder cancer stage into four groups and from healthy volunteers (n = 30). Histopathology examination, bilharzias antibody detection, urine cytology, and mRNA expression of S100A genes were estimated for all subjects by real time polymerase chain reaction (RT-PCR). Results indicate that each of the investigated S100A genes can be used as diagnostic marker for bladder cancer. Both S100A4 and S100A6 can be used to differentiate between different stages of bladder cancer. S100A7 can be used for the diagnosis of squamous cell carcinoma. Both S100A8 and S100A9 can be used for detection of invasive bladder carcinoma while S100A11 can be used for early detection of superficial bladder carcinoma. The overall sensitivity and specificity for the studied S100A genes ranged from 73 to 90 and 84 to 92, respectively. The combined use of urine cytology with the investigated S100A genes increased sensitivity from 56 % up to a range of 87-96 %. In conclusion, serum S100A genes can be useful as potential serological biomarkers for bladder cancer, and combined use of urine cytology with S100A genes can improve the sensitivity for detection of bladder cancer.

Esber N, Le Billan F, Resche-Rigon M, et al.
Ulipristal Acetate Inhibits Progesterone Receptor Isoform A-Mediated Human Breast Cancer Proliferation and BCl2-L1 Expression.
PLoS One. 2015; 10(10):e0140795 [PubMed] Free Access to Full Article Related Publications
The progesterone receptor (PR) with its isoforms and ligands are involved in breast tumorigenesis and prognosis. We aimed at analyzing the respective contribution of PR isoforms, PRA and PRB, in breast cancer cell proliferation in a new estrogen-independent cell based-model, allowing independent PR isoforms analysis. We used the bi-inducible human breast cancer cell system MDA-iPRAB. We studied the effects and molecular mechanisms of action of progesterone (P4) and ulipristal acetate (UPA), a new selective progesterone receptor modulator, alone or in combination. P4 significantly stimulated MDA-iPRA expressing cells proliferation. This was associated with P4-stimulated expression of the anti-apoptotic factor BCL2-L1 and enhanced recruitment of PRA, SRC-1 and RNA Pol II onto the +58 kb PR binding motif of the BCL2-L1 gene. UPA decreased cell proliferation and repressed BCL2-L1 expression in the presence of PRA, correlating with PRA and SRC1 but not RNA Pol II recruitment. These results bring new information on the mechanism of action of PR ligands in controlling breast cancer cell proliferation through PRA in an estrogen independent model. Evaluation of PR isoforms ratio, as well as molecular signature studies based on PRA target genes could be proposed to facilitate personalized breast cancer therapy. In this context, UPA could be of interest in endocrine therapy. Further confirmation in the clinical setting is required.

Bartosch C, Monteiro-Reis S, Vieira R, et al.
Endometrial Endometrioid Carcinoma Metastases Show Decreased ER-Alpha and PR-A Expression Compared to Matched Primary Tumors.
PLoS One. 2015; 10(8):e0134969 [PubMed] Free Access to Full Article Related Publications
Patients with endometrial endometrioid carcinoma (EEC) that present with advanced primary disease and develop recurrences have a poor outcome. The phenotype of EEC metastases and recurrences is poorly studied. We evaluated the morphological features and ER-alpha/PRA/p53 immunohistochemical expression of a sample of 45 EEC metastases compared to matched primary tumors. Additionally, we studied methylation levels of ER-alpha/PRA gene promoters. The distribution of histological FIGO grade was significantly different in metastases, which disclosed higher grade than primary tumors (p = 0.005). Mitotic index was significantly lower in metastases compared to matched primary tumors (p<0.001). ER-alpha (p = 0.002) and PRA (p<0.001) median H-scores were significantly lower in metastases than in matched primary EECs, but there was no significant difference concerning p53 expression (p = 0.056). ER-alpha/PRA expression differences did not correlate with differences in metastases morphology. ER-alpha/PRA gene promoter levels were globally low (range: 0% to 11.9%). One case showed higher ER-alpha gene promoter methylation in metastasis compared to matched EEC primary tumor. Regarding PRA, there was a significant higher frequency of its promotor methylation in metastases compared to primary tumors (51.6% vs. 22.7%, p = 0.022). In conclusion, EEC metastatic disease displays phenotypic changes along with ER-alpha and PRA decreased expression compared to primary tumors. ER-alpha and PRA gene promoter methylation seems to play a limited role in the etiology of these alterations. PR expression assessment for hormonal treatment decision of patients with advanced tumors, may be more adequate in metastases than in EEC primary tumors.

Huang J, Li H, Ren G
Epithelial-mesenchymal transition and drug resistance in breast cancer (Review).
Int J Oncol. 2015; 47(3):840-8 [PubMed] Related Publications
Breast cancer is the leading cause of cancer death in women worldwide. Insensitivity of tumor cells to drug therapies is an essential reason arousing such high mortality. Epithelial-mesenchymal transition (EMT) is defined by the loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. It is well known that EMT plays an important role in breast cancer progression. Recently, mounting evidence has demonstrated involvement of EMT in antagonizing chemotherapy in breast cancer. Here, we discuss the biological significance and clinical implications of these findings, with an emphasis on novel approaches that effectively target EMT to increase the efficacy of anticancer therapies.

Nepomuceno AI, Shao H, Jing K, et al.
In-depth LC-MS/MS analysis of the chicken ovarian cancer proteome reveals conserved and novel differentially regulated proteins in humans.
Anal Bioanal Chem. 2015; 407(22):6851-63 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer (OVC) remains the most lethal gynecological malignancy in the world due to the combined lack of early-stage diagnostics and effective therapeutic strategies. The development and application of advanced proteomics technology and new experimental models has created unique opportunities for translational studies. In this study, we investigated the ovarian cancer proteome of the chicken, an emerging experimental model of OVC that develops ovarian tumors spontaneously. Matched plasma, ovary, and oviduct tissue biospecimens derived from healthy, early-stage OVC, and late-stage OVC birds were quantitatively characterized by label-free proteomics. Over 2600 proteins were identified in this study, 348 of which were differentially expressed by more than twofold (p ≤ 0.05) in early- and late-stage ovarian tumor tissue specimens relative to healthy ovarian tissues. Several of the 348 proteins are known to be differentially regulated in human cancers including B2M, CLDN3, EPCAM, PIGR, S100A6, S100A9, S100A11, and TPD52. Of particular interest was ovostatin 2 (OVOS2), a novel 165-kDa protease inhibitor found to be strongly upregulated in chicken ovarian tumors (p = 0.0005) and matched plasma (p = 0.003). Indeed, RT-quantitative PCR and Western blot analysis demonstrated that OVOS2 mRNA and protein were also upregulated in multiple human OVC cell lines compared to normal ovarian epithelia (NOE) cells and immunohistochemical staining confirmed overexpression of OVOS2 in primary human ovarian cancers relative to non-cancerous tissues. Collectively, these data provide the first evidence for involvement of OVOS2 in the pathogenesis of both chicken and human ovarian cancer.

Mote PA, Gompel A, Howe C, et al.
Progesterone receptor A predominance is a discriminator of benefit from endocrine therapy in the ATAC trial.
Breast Cancer Res Treat. 2015; 151(2):309-18 [PubMed] Related Publications
Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in breast cancer risk. The two progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB proteins was determined by dual immunofluorescence histochemistry in archival breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous hormone use (menopausal hormone treatment, MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on tamoxifen, but not anastrozole (mean lnPRA:PRB ratio; HR (95 % CI) tamoxifen 2.45 (1.20-4.99); p value 0.02; anastrozole 0.80 (0.36-1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with MHT use, and that PRA predominance can discriminate those women who will relapse earlier on tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in breast cancer progression and relative benefit from endocrine treatment.

Martínez-Aguilar J, Clifton-Bligh R, Molloy MP
A multiplexed, targeted mass spectrometry assay of the S100 protein family uncovers the isoform-specific expression in thyroid tumours.
BMC Cancer. 2015; 15:199 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mounting evidence demonstrates a causal role for S100 proteins in tumourigenesis and several S100 isoforms have shown utility as biomarkers of several types of cancer. The S100 family is comprised of 21 small isoforms, many of them implicated in important cellular functions such as proliferation, motility and survival. Furthermore, in vivo experiments have proven the role of S100 proteins in tumour growth and disease progression, while other studies have shown their prognostic value and involvement in resistance to chemotherapy drugs. Taken together, all these aspects highlight S100 proteins as potential therapeutic targets and as a promising panel of cancer biomarkers. In this work, we have developed a mass spectrometry (MS)-based method for the multiplexed and specific analysis of the entire S100 protein family in tumour tissues and have applied it to investigate the expression of S100 isoforms in the context of thyroid cancer, the main endocrine malignancy.
METHODS: Selected Reaction Monitoring (SRM)-MS and stable isotope labelling/label-free analysis were employed to investigate the expression of the 21 S100 protein isoforms in thyroid tissue samples. Specimens included 9 normal thyroid tissues and 27 tumour tissues consisting of 9 follicular adenomas (FA), 8 follicular carcinomas (FTC) and 10 papillary carcinomas (PTC).
RESULTS: The multiplexed and targeted mass spectrometry method led to the detection of eleven S100 protein isoforms across all tissues. Label- and label-free analyses showed the same significant differences and results were confirmed by western blot. S100A6, S100A11 and its putative interaction partner annexin A1 showed the highest overexpression in PTC compared to normal thyroid. S100A13 was also elevated in PTC. Reduced S100A4 expression was observed in FA compared to all other tissues. FA and FTC showed reduction of S100A10 and annexin A2 expression.
CONCLUSIONS: Targeted mass spectrometry allows the multiplexed and specific analysis of S100 protein isoforms in tumour tissue specimens. It revealed S100A13 as a novel candidate PTC biomarker. Results show that S100A6, S100A11 and Annexin A1 could help discriminate follicular and papillary tumours. The diagnostic and functional significance of S100A4 and S100A10 reduction in follicular tumours requires further investigation.

Lyu XJ, Li HZ, Ma X, et al.
Elevated S100A6 (Calcyclin) enhances tumorigenesis and suppresses CXCL14-induced apoptosis in clear cell renal cell carcinoma.
Oncotarget. 2015; 6(9):6656-69 [PubMed] Free Access to Full Article Related Publications
Clear cell renal cell carcinoma (ccRCC) is often resistant to existing therapy. We found elevated S100A6 levels in ccRCC tissues, associated with higher grade pathological features and clinical stages in ccRCC patients. Knockdown of S100A6 inhibited cell proliferation in vitro and tumor growth in vivo. Gene expression profiling suggests a novel function of S100A6 in suppressing apoptosis, as well as a relationship between S100A6 and CXCL14, a pro-inflammatory chemokine. We suggest that the S100A6/CXCL14 signaling pathway is a potential therapeutic target in ccRCC.

Yoneda T, Hiasa M, Nagata Y, et al.
Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain.
Biochim Biophys Acta. 2015; 1848(10 Pt B):2677-84 [PubMed] Free Access to Full Article Related Publications
Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

Miao W, Liu X, Wang H, et al.
p53 upregulated modulator of apoptosis sensitizes drug-resistant U251 glioblastoma stem cells to temozolomide through enhanced apoptosis.
Mol Med Rep. 2015; 11(6):4165-73 [PubMed] Free Access to Full Article Related Publications
Malignant glioma is a highly aggressive brain tumor with a poor prognosis. Chemotherapy has been observed to prolong overall survival rate and temozolomide (TMZ), a promising chemotherapeutic agent for treating glioblastoma (GBM), possesses the most effective clinical activity at present, although drug resistance limits its clinical outcome. Growing evidence supports the concept that initial and recurrent GBM may derive from glioblastoma stem cells, which may be responsible for drug resistance. However, the molecular mechanisms underlying this resistance remain to be elucidated. In the present study, a TMZ‑resistant GBM cell line, U251R, was developed and subsequently divided into two subpopulations according to the CD133 immunophenotype. No significant difference was identified in the expression of O6‑methylguanine‑DNA‑methyltransferase (MGMT) between CD133+ U251R cells and CD133‑ U251R cells, whereas the CD133+ cell population was more resistant to TMZ‑induced growth inhibition and cell death. TMZ achieves its cytotoxic effect by inducing DNA lesions and p53 upregulated modulator of apoptosis (PUMA) is an essential mediator of DNA damage‑induced apoptosis independently of p53 status. Therefore, whether PUMA effectively enhances growth suppression and induces apoptosis when combined with TMZ was investigated. Consequently, it was found that adenoviruses expressing wild‑type‑PUMA not only lead to the apoptosis of CD133+ U251R cells alone, but also significantly increase their sensitivity toward TMZ by elevating the Bcl‑2‑associated X protein/B‑cell lymphoma‑2 ratio without alterations in MGMT expression. Therefore, PUMA may be a suitable target for intervention to improve the therapeutic efficacy of TMZ.

Artimani T, Saidijam M, Aflatoonian R, et al.
Estrogen and progesterone receptor subtype expression in granulosa cells from women with polycystic ovary syndrome.
Gynecol Endocrinol. 2015; 31(5):379-83 [PubMed] Related Publications
We evaluated gene expression of estrogen and progesterone nuclear receptors in granulosa cells (GCs) of polycystic ovary syndrome (PCOS) women compared to women with normal cycling ovaries (control group) to achieve a better understanding of ovarian steroid status in patients with PCOS. In this prospective study, 40 patients with PCOS and 40 women with normal ovulatory function who underwent in vitro fertilization (IVF) for treatment of tubal and/or male infertility were recruited. Follicular fluid was collected from patients and GCs were isolated from follicular fluid and then were purified with Micro Beads conjugated to monoclonal anti-human CD45 antibodies. RNA was extracted and reverse transcription was performed. Gene expression of estrogen and progesterone receptors was determined by quantitative real time PCR (qRT-PCR). Estrogen receptor β (ERβ) expression was significantly higher than ERα expression in both groups (p < 0.002). ERα and ERβ mRNA expression in PCOS was significantly lower than control group (p < 0.002). The expression levels of PRA and PRB in PCOS was significantly lower than control group (p < 0.002). In conclusion, a significant reduction of these genes in GCs from follicles of women with PCOS could be considered as a sign for maturation defect or follicular arrest in GCs.

Coumans JV, Gau D, Poljak A, et al.
Profilin-1 overexpression in MDA-MB-231 breast cancer cells is associated with alterations in proteomics biomarkers of cell proliferation, survival, and motility as revealed by global proteomics analyses.
OMICS. 2014; 18(12):778-91 [PubMed] Free Access to Full Article Related Publications
Despite early screening programs and new therapeutic strategies, metastatic breast cancer is still the leading cause of cancer death in women in industrialized countries and regions. There is a need for novel biomarkers of susceptibility, progression, and therapeutic response. Global analyses or systems science approaches with omics technologies offer concrete ways forward in biomarker discovery for breast cancer. Previous studies have shown that expression of profilin-1 (PFN1), a ubiquitously expressed actin-binding protein, is downregulated in invasive and metastatic breast cancer. It has also been reported that PFN1 overexpression can suppress tumorigenic ability and motility/invasiveness of breast cancer cells. To obtain insights into the underlying molecular mechanisms of how elevating PFN1 level induces these phenotypic changes in breast cancer cells, we investigated the alteration in global protein expression profiles of breast cancer cells upon stable overexpression of PFN1 by a combination of three different proteome analysis methods (2-DE, iTRAQ, label-free). Using MDA-MB-231 as a model breast cancer cell line, we provide evidence that PFN1 overexpression is associated with alterations in the expression of proteins that have been functionally linked to cell proliferation (FKPB1A, HDGF, MIF, PRDX1, TXNRD1, LGALS1, STMN1, LASP1, S100A11, S100A6), survival (HSPE1, HSPB1, HSPD1, HSPA5 and PPIA, YWHAZ, CFL1, NME1) and motility (CFL1, CORO1B, PFN2, PLS3, FLNA, FLNB, NME2, ARHGDIB). In view of the pleotropic effects of PFN1 overexpression in breast cancer cells as suggested by these new findings, we propose that PFN1-induced phenotypic changes in cancer cells involve multiple mechanisms. Our data reported here might also offer innovative strategies for identification and validation of novel therapeutic targets and companion diagnostics for persons with, or susceptibility to, breast cancer.

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