Cell, Molecular, and Tumor Biology最新文献

{"title":"Abstract B67: Overexpression of claudin-3 tight junction protein in endometrial cancer cell lines and tumor tissues derived from African American women","authors":"M. E. Cuevas, M. Todd","doi":"10.1158/1538-7755.DISP17-B67","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B67","url":null,"abstract":"According to the American Cancer Society (2017), endometrial cancer is the most common type of reproductive tumor in the US. Notably, whereas the incidence of endometrial cancer is similar in women of different races, the mortality rate is significantly higher in African American women. Currently, the molecular etiology of this disease is not well understood nor is there an explanation as to the disparity between the clinical outcomes for African American women and women of other races. Thus, the purpose of the current study was to determine (1) the expression of claudin-3 mRNA and protein in a panel of endometrial cancer cell lines and (2) the expression of claudin-3 protein in matched pairs of normal and tumor tissues derived from African American women with endometrial cancer. RT-PCR was used to measure claudin-3 mRNA expression, and immunoblotting was used to evaluate claudin-3 protein levels. We observed overexpression of claudin-3 protein in 4 of the 10 endometrial cancer cell lines and in 4 of the 6 primary endometrial cancer tissues (relative to their matched normal control tissues). Consistent with the immunoblotting data, the levels of claudin-3 mRNA were elevated in the same 4 cell lines that showed overexpression of the protein. These data suggest that increased transcription of the claudin-3 gene is responsible for the elevated levels of the claudin-3 protein. Consistent observations of elevated claudin-3 gene expression may indicate its use as a diagnostic marker. The finding of claudin-3 overexpression in the majority of endometrial tumor tissues suggests a role for tight junction disruption in the development of endometrial cancer in African American women. Citation Format: Maria E. Cuevas, Maria C. Todd. Overexpression of claudin-3 tight junction protein in endometrial cancer cell lines and tumor tissues derived from African American women [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B67.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"2013 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114639152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B64: Race and prostate cancer: miRNA isoforms and tRNA fragments could hold some of the answers","authors":"Rogan Magee, Aristeidis G. Telonis, Phillipe Loher, Eric Londin, I. Rigoutsos","doi":"10.1158/1538-7755.DISP17-B64","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B64","url":null,"abstract":"Prostate cancer is the most frequently occurring cancer in men. Compared to White (Wh) men, Black/African American (B/Aa) men exhibit higher mortality and higher incidence rates of prostate cancer. This difference remains even after modifiable factors are taken into account, which suggests an underlying cause. Recent studies greatly improved our understanding of the biochemistry of prostate cancer. Nonetheless, many open questions remain, especially with regard to the molecular underpinnings of the observed race disparities. In this study, we analyzed 526 transcriptomic datasets from prostate adenocarcinoma (PRAD) patients. We obtained the data from The Cancer Genome Atlas (TCGA) repository. We focused on two categories of noncoding RNAs that regulate messenger RNA (mRNA) and protein abundance: (1) microRNAs (miRNAs) and their isoforms (isomiRs) and (2) tRNA-derived fragments (tRFs). Both tRFs and isomiRs regulate mRNAs and their proteins through the RNA induced silencing complex (RISC). Furthermore, tRFs have a number of other regulatory roles in healthy and diseased cells, including direct physical interactions with ribosomal proteins and initiation factors. Notably, we have demonstrated and reported previously that isomiRs and tRFs are constitutive and transcribed in a manner that depends strongly on a person9s gender, race, and population origin, as well as on tissue type, tissue state, and disease type/subtype. Our analyses of the TCGA PRAD datasets revealed that both isomiRs and tRFs are disrupted in PRAD. By extension, the regulatory networks that link isomiRs and tRFs to mRNAs are also disrupted. We also uncovered transcriptomic differences and differential regulatory relationships that are aligned with patient race. Moreover, we found that the molecular differences between B/Aa and Wh PRAD patients extend to normal prostate tissue as well. These findings mirror earlier results that we obtained from both healthy individuals and cancer patients. The race-dependent regulatory profiles highlight differences in the underlying biology in B/Aa and Wh individuals that have yet to be explored. For example, the corresponding molecules could potentially be leveraged as novel biomarkers or alternative therapeutic targets. This study represents the first characterization of isomiRs and tRFs in a large cohort of PRAD patients. Citation Format: Rogan G. Magee, Aristeidis G. Telonis, Phillipe Loher, Eric Londin, Isidore Rigoutsos. Race and prostate cancer: miRNA isoforms and tRNA fragments could hold some of the answers [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B64.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128535793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B70: Thymoquinone regulates cytochrome P450 genes involved in prostate cancer disparity","authors":"S. Singh, J. Lillard, Rajesh Singh","doi":"10.1158/1538-7755.DISP17-B70","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B70","url":null,"abstract":"African American (AA) men have a higher incidence and greater mortality from prostate cancer (PCa) than Caucasian American (CA) men. The factor influencing the racial disparity is not clearly understood and is probably genetic variation attributed to the disease. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of the genes of the enzymes involved in androgen biosynthesis and metabolism, such as CYP3A4, CYP3A7, and CYP17A1. Although several inhibitors are approved for CYPs genes, the major drawback of these inhibitors is they contain the steroid scaffold, which contributes to the undesirable side effects (dyspnea, edema, contusion, etc.) observed in patients. In this regard, using nonsteroid scaffolds such as natural compound acts as a more potent inhibitor and interacts more selectively with the cytochrome P450 family. In this study, our data showed the effect of natural compound thymoquinone (TQ), a constituent of Nigella sativa (black seed), on CYP3A4, CYP3A7, and CYP17A1 genes in PCa cells, and found that TQ-treated cells significantly downregulated the expression of CYP3A4, CYP3A7, and CYP17A1 in MDA PCa 2b and E006AA-hT (African American) compared to LNCaP (Caucasian) cell lines. These findings were further confirmed by flow cytometry, Western blots, and immunofluorescence. These studies suggested that TQ could be the potent inhibitor of the active sites of the cytochrome P450 enzymes, which are an important target in the treatment of PCa. Additionally, knowledge of the PCa susceptibility genes (CYPs) could be used to identify individuals at risk of developing PCa with poor outcomes for heightened screening or prevention modalities and to identify optimal treatment strategies for men of African descent. Citation Format: Santosh K. Singh, James W. Lillard, Jr., Rajesh Singh. Thymoquinone regulates cytochrome P450 genes involved in prostate cancer disparity [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B70.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132938198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B61: c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive prostate cancer in men of African ancestry","authors":"D. Das, A. Orunmuyi, G. Ogun, S. Adebayo, A. A. Salako, Adeodat Ilboudo, C. Bach, E. Olapade-Olaopa, O. Ogunwobi","doi":"10.1158/1538-7755.DISP17-B61","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B61","url":null,"abstract":"Prostate cancer is the 2nd most common cancer in the world for men. For reasons still unclear, aggressive PCa disproportionately affects males of African ancestry (MoAA). Incidence and mortality rates are highest in MoAA as they have consistently shown a 2.3-3.0-fold higher risk of mortality compared to Caucasian men (CM). This aggressiveness of PCa may be due to specific biologic factors. Located downstream of c-Myc at chromosome 8q24 is PVT1, which encodes miR-1207-3p. Studies have shown that PVT1/MYC cooperation is a fundamental feature in all cancers with 8q24 amplification, and 98% of the 8q24 amplicons contained concurrent amplification of the MYC and PVT1 loci. Moreover, MYC has been linked to PCa aggressiveness and has been reported to be downstream of AR in some PCa. However, the mechanisms regulating c-MYC have never been studied in MoAA. We recently demonstrated that miR-1207-3p directly binds to FNDC1 to regulate a novel FNDC1/FN1/AR pathway upregulated in metastatic prostate cancer (PCa). However, the mechanisms regulating c-Myc in PCa remain unclear, and the relevance of our novel and clinically significant miR-1207-3p molecular pathway in PCa in MoAA is unknown. The aim of this study was to determine if c-Myc is regulated and therapeutically targetable via the miR-1207-3p/FNDC1/FN1/AR pathway in aggressive PCa in MoAA. We used qPCR, immunoblotting, RNA pulldown, proliferation, migration, and apoptosis assays to evaluate miR-1207-3p regulation of c-Myc in aggressive PCa in MoAA. Also, miR-1207-3p, FNDC1, FN1, AR, and c-Myc expression was analyzed in prostate tissues (normal = 21; benign = 41; tumor = 26) of patients who received prostatectomy or transrectal ultrasound-guided biopsies at the University College Hospital, Ibadan, Nigeria, a sub-Saharan Black African population. Seventeen patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Review Board-approved protocols. ANOVA, student9s t-test, and Tukey post-hoc tests were used for statistical analysis. Prostate tissue analysis revealed that underexpression of miR-1207-3p and the overexpression of FNDC1, FN1, AR, and c-Myc is significantly associated with aggressive PCa in MoAA. Also, miR-1207-3p was underexpressed while FNDC1 and c-MYC were overexpressed in tumors with Gleason score ≥8 in comparison to those with Gleason score 75% in the MoAA-derived indolent E006AA PCa cell line and the MoAA-derived aggressive/castration-resistant E006AA-hT PCa cell line, indicating that c-Myc is downstream of AR. c-Myc expression is higher in the E006AA-hT PCa cell line when compared to the E006AA PCa cell line, suggesting that c-Myc is associated with aggressive PCa. Moreover, NB1207 significantly inhibited migration and induced apoptosis in E006AA and E006AA-hT PCa cell lines. Next, we compared the efficacy of NB1207 in inhibiting proliferation to the commercially available drugs for treatment of CPRC (enzalutamide and abiraterone). NB1207 i","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"23 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133174972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract C44: Epigenetic regulation of CRLF2 oncogene expression by Casein Kinase II (CK2) signaling in B-cell acute lymphoblastic leukemia that occurs at high frequency in Hispanic children","authors":"Chunhua Song, Z. Ge, K. Payne, S. Dovat","doi":"10.1158/1538-7755.DISP17-C44","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-C44","url":null,"abstract":"B-cell acute lymphoblastic leukemia (B-ALL) occurs more frequently in Hispanic children as compared to non-Hispanic whites. The specific subtype of B-ALL that is caused by overexpression of CRLF2 (CRLF2 B-ALL), occurs 5 times more frequently in Hispanic children as compared to the others. Since this type of B-ALL is associated with poor prognosis, the death rate of B-ALL is 39% higher in Hispanic children than in non-Hispanic whites. Thus, understanding the molecular mechanisms that regulate CRLF2 expression in CRLF2 B-ALL is essential for the development of targeted therapy for this disease. Our previous work determined that transcription of CRLF2 is negatively regulated by a tumor-suppressor protein, Ikaros. Ikaros deregulation is a feature of over 80% of CRLF2 B-ALL. Here we present evidence that Ikaros-mediated repression of CRLF2 transcription in B-ALL in Hispanic children is regulated by Casein Kinase II (CK2). CK2 is an oncogenic kinase that is overexpressed in B-ALL. We have previously shown that CK2 can directly phosphorylate Ikaros and that phosphorylation by CK2 can impair Ikaros function as transcriptional regulator. We tested whether inhibition of CK2 affects the ability of Ikaros to regulate CRLF2 transcription. Molecular inhibition by shRNA that targets the catalytic subunit of CK2, as well as pharmacologic inhibition of CK2 by the specific inhibitor, CX-4945, resulted in reduced expression of CRLF2 as measured by qRT-PCR. This was associated with increased Ikaros binding to the CRLF2 promoter as measured by quantitative chromatin immunoprecipitation (qChIP). To determine whether Ikaros function is essential for CRLF2 repression following CK2 inhibition, we compared expression of CRLF2 in cells that have Ikaros knocked-down by shRNA vs. cells with control shRNA, following treatment with CX-4945. Results showed that Ikaros knockdown abolished the ability of CK2 inhibitors to repress transcription of CRLF2 in B-ALL. These results demonstrate that Ikaros is an essential component of CK2 signaling that regulates CRLF2 expression. Analysis of the epigenetic signature at the CRLF2 promoter performed by serial qChIP assays showed that increased Ikaros binding to the CRLF2 promoter, following CK2 inhibition, is associated with enrichment for the H3K9me3 histone modification, which is a marker of repressive chromatin. In conclusion, we demonstrate that expression of the CRLF2 oncogene in acute leukemia that disproportionally occurs in Hispanic children is epigenetically regulated by the CK2-Ikaros axis. In CRLF2 B-ALL, Ikaros-mediated repression of CRLF2 is impaired due to overexpression of CK2. Treatment of CRLF2 B-ALL with CK2 inhibitors restores Ikaros tumor suppressor function, resulting in CRLF2 repression. Results identified a signaling network that regulates CRLF2 expression and suggest that restoration of Ikaros activity with CK2 inhibitors can be a therapeutic approach for CRLF2 B-ALL to reduce the health disparity for Hispanic chi","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121294436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR01: Distinct genomic alterations in prostate cancer of African American men","authors":"A. Dobi, G. Petrovics, Hua Li, D. Young, Yongmei Chen, J. Kagan, S. Srivastava, R. Ebner, I. Rosner, J. Cullen, M. Freedman, I. Sesterhenn, Z. Szallasi, S. Srivastava","doi":"10.1158/1538-7755.DISP17-PR01","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-PR01","url":null,"abstract":"Background: Emerging observations highlight distinct biology of prostate cancer (CaP) among men of different ethnicities and races. Studies including reports from our institute have demonstrated remarkable ethnic/racial differences in the frequency of ERG oncogenic activation, one of the most common and widely studied CaP driver genes. Similarly, deletion of the PTEN tumor suppressor gene, an established cancer driver gene alteration, was shown to be more prevalent among men of European ancestry. We have reported the cumulative analyses of 435 patients (whole-genome sequencing [WGS]: 14, FISH evaluations: 101, SNP array: 320) comparing CaP genomes of African American and Caucasian American patients. An AA CaP genome associated minimum deletion site on 3q13.31 was identified by WGS and mapped to the Limbic System-Associated Membrane Protein (LSAMP) gene locus using the TCGA SNP array data of 44 AA and 260 CA tumors. Further, we also noted the AA CaP genome association of the Chromodomain Helicase DNA Binding Protein 1(CHD1) gene deletion. Methods: The frequency and prognostic associations of LSAMP, CHD1, and PTEN deletions was evaluated by FISH analyses in prostate tumor tissue microarray (TMA) with up to 20 years of follow-up. The TMA represented normal and tumor foci (1000+ cores) sampled by 2-3 cores including the spectrum of cell morphology and tumor pathology in matched cohort of 42 AA and 59 CA patients. ERG was evaluated in the same TMA by immunohistochemistry. Evaluation of ERG was extended to the assessment of whole mounted prostate sections of 336 AA and 594 CA patients from the equal-access military health care system, in which disparities in socioeconomic status, health awareness, and physical activity are minimized. Results: AA CaP genome-associated recurrent deletions of LSAMP (26% AA vs. 7% CA, p=0.006) and CHD1 (29% AA vs. 10% CA p=0.017) genes were identified. AA CaP patients harboring these genomic deletions in their CaP showed significantly higher risk of rapid disease progression as measured by biochemical recurrence. Consistent with previous reports, we noted significantly lower frequency of PTEN deletions (15% AA vs. 63% CA) and ERG expression (26% AA vs. 64%) in prostate cancers among AA men. In-depth evaluation of ERG frequencies in the context of multifocal disease provided definitive evidence for the difference in the frequency of ERG between AA (23%) and CA (49%) patients from the equal-access military health care system. Conclusions: Our study underscores that the biology of CaP has to be taken into consideration when new diagnostic and prognostic markers and therapeutic approaches are being developed in order to realize the true potential of precision medicine for all cancer patients. Note: This abstract was not presented at the conference. Citation Format: Albert Dobi, Gyorgy Petrovics, Hua Li, Denise Young, Yongmei Chen, Jacob Kagan, Sudhir Srivastava, Reinhard Ebner, Inger L. Rosner, Jennifer Cullen, Matthew L. Free","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128949077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B57: Distinct genomic alterations in prostate cancer of African American men","authors":"A. Dobi, G. Petrovics, Hua Li, D. Young, Yongmei Chen, J. Kagan, S. Srivastava, R. Ebner, I. Rosner, J. Cullen, M. Freedman, I. Sesterhenn, Z. Szallasi, S. Srivastava","doi":"10.1158/1538-7755.disp17-b57","DOIUrl":"https://doi.org/10.1158/1538-7755.disp17-b57","url":null,"abstract":"","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"110 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123673111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B71: Biologic for the treatment of CRLF2 B-cell acute lymphoblastic leukemia to reduce pediatric cancer health disparities","authors":"Cornelia Stoian, J. Coats, V. Vidales, J. Personius, E. Chirshev, Hossam R. Alkashgari, Ineavely Báez, L. Liu, Hannah Choi, S. Dovat, K. Payne","doi":"10.1158/1538-7755.DISP17-B71","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B71","url":null,"abstract":"B-cell acute lymphoblastic leukemia (B-ALL) with genetic alterations leading to overexpression of the cytokine receptor, CRLF2, is associated with poor outcomes. CRLF2 B-ALL occurs 5 times more often in Hispanic children than others, is prevalent in adolescents and young adults, and is associated with a high relapse rate and poor prognosis. In patients, the CRLF2 receptor is stimulated by circulating TSLP cytokine. This stimulation is not provided by classic patient-derived xenograft (PDX) models because the TSLP present in mice has low homology to human TSLP and does not activate the CRLF2 receptor. We developed a novel PDX model of CRLF2 B-ALL that allows us to vary circulating levels of human TSLP (+T PDX). When we injected primary CRLF2 B-ALL cells from Hispanic pediatric patients into +T PDX with circulating human TSLP (hTSLP) levels similar to pediatric leukemia patients (~4-10 pg/ml), they engrafted well and showed a gene expression pattern that was more similar to the original patient sample than when injected into classic PDX. To our surprise, when +T PDX expressed physiologic but elevated levels of hTSLP (> 40 pg/ml, upper end of range reported in healthy children), CRLF2 B-ALL cells were essentially eliminated, but grew robustly in PDX without hTSLP (-T PDX). These results have been observed in 4 independent experiments for a total of 17 +T PDX and 12 -T PDX mice produced using CRLF2 B-ALL cells from two different Hispanic pediatric patients with CRLF2 B-ALL. Our next step was to identify the mechanism through which hTSLP exerts its antileukemia effects. Binding of hTSLP to CRLF2 and associated receptor components activates the JAK-STAT5 pathway as well as the PI3K/AKT/mTOR pathway. JAK-STAT signaling is known to upregulate the Suppressor of Cytokine Signaling (SOCS) genes. SOCS genes encode a family of proteins that regulate cytokine signaling via negative feedback through multiple mechanisms. Flow cytometry analysis showed that the SOCS family proteins, SOCS1, SOCS3, and CISH, were upregulated in the CRLF2 B-ALL cell lines MUTZ5 and CALL-4 following 3 days of culture with hTSLP, as compared to controls without hTSLP. Similar results were obtained using CRLF2 B-ALL cells from two Hispanic pediatric patients. Whole-genome RNA sequencing of primary CRLF2 B-ALL cells from a Hispanic pediatric patient also showed upregulation of SOCS1, SOCS3, and CISH mRNA. Next, we determined whether the upregulation of SOCS proteins was accompanied by the deactivation of hTSLP-induced CRLF2 signaling. CRLF2 B-ALL cell lines were cultured with or without hTSLP for 3 days to allow SOCS upregulation, then harvested and assessed for their ability to activate the JAK/STAT5 and PI3/AKT/mTOR pathways following hTSLP stimulation. Leukemia cells cultured for 3 days without hTSLP retained their ability to induce phosphorylation of STAT5 and ribosomal protein S6 (downstream of PI3/AKT/mTOR). In contrast, leukemia cells cultured with hTSLP showed no phosphorylation","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"50 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115231525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B76: High glucose induces breast cancer progression through upregulating PP2Cδ","authors":"Ke Wu, Xiaoting Yu, Xianghua Yi, Lynn Ma, Y. Elshimali, Yanjun Liu, Donghui Zhu, Yong Wu, J. Vadgama","doi":"10.1158/1538-7755.DISP17-B76","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B76","url":null,"abstract":"Breast cancer has a high incidence worldwide. African-American and Hispanic/Latina women have higher mortality from breast cancer than other ethnic groups. Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer. Diabetes and cancer share many risk factors, but the pathophysiologic relationship between the two diseases is incompletely understood in detail. We observed that exposure of cultured transformed (MCF-7) and normal (MCF-12A) breast epithelial cells to clinically relevant levels of glucose (HG, 22 mM) dramatically suppresses the tumor suppressor p53 acetylation, and, consequently, additively promotes tumor cell proliferation, migration, and invasion. Importantly, we found that activation of nuclear phosphatase PP2Cδ (Ppm1d, WIP1) plays a role in the enhancing effects of HG on aggressive phenotypes of these cells. The mechanisms underlying high-glucose stimulation of PP2Cδ involve classical/novel PKCs activation and its downstream target protein GSK3β phosphorylation and inactivation. In addition, HG-induced reactive oxygen species (ROS) generation and subsequent NF-κB activation play a partial role in HG induction of PP2Cδ. HG inhibition of p53 activity and DNA damage-induced apoptosis, as well as induction of cancer cell proliferation, migration, and invasion, were significantly blocked by CCT007093, a known PP2Cδ inhibitor. We conclude that hyperglycemia, via PKC/GSK3β and ROS/NF-κB pathways that are involved in PP2Cδ activation, suppresses the tumor suppressor p53 function and inhibits DNA damage-induced apoptosis, inducing proliferation in the epithelium and the development of breast cancer. Citation Format: Ke Wu, Xiaoting Yu, Xianghua Yi, Lynn Ma, Yahya Elshimali, Yanjun Liu, Donghui Zhu, Yong Wu, Jaydutt V. Vadgama. High glucose induces breast cancer progression through upregulating PP2Cδ [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B76.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124563960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B55: Tumor-derived MCP-1 regulates invasiveness in triple-negative breast cancer via the MAP kinase pathway","authors":"P. Dutta, Kimberly Paico, Yanyuan Wu, Marianna Sarkissyan, J. Vadgama","doi":"10.1158/1538-7755.DISP17-B55","DOIUrl":"https://doi.org/10.1158/1538-7755.DISP17-B55","url":null,"abstract":"Background : Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer compared to other breast cancer subtypes. The frequency of TNBC expression is highest in young African-American women, leading to significant cancer health disparity in this population. Furthermore, TNBC is difficult to treat due to lack of known receptor targets at protein or gene level. Hence, it is imperative to identify novel therapeutic strategies for treatment of TNBC. Here we aim to show that the Monocyte Chemoattractant Protein -1 (MCP-1) is a reliable biochemical marker to assess TNBC progression. Experimental Design : We employed ELISA method to measure secreted MCP-1 in cell conditioned media, and real-time PCR to determine the mRNA status of MCP-1 in different TNBC cell lines. Boyden chamber assay was used to determine the effect of recombinant MCP-1 on cellular invasiveness. Immunohistochemistry staining was utilized for detecting protein of interest in tissue samples from breast cancer patients. MCP-1 knockdown was performed using lentiviral vector with shRNA targeting MCP-1 coding regions. RNAseq was performed with recombinant human MCP-1. Results : Our data show that MCP-1 is upregulated in TNBC cell lines, both transcriptionally and in secreted protein levels compared to ER-positive cell line, MCF-7. Breast cancer patients also showed high expression of MCP-1. MCP-1 treatment induced MDA-MB-231 and MCF-7 cell invasion, without affecting cell proliferation. Small-molecule antagonists against chemokine receptor 2 (CCR2), cognate receptor for MCP-1, and the MAP kinase pathway inhibitor U0106 negatively affected MDA-MB-231 cell invasion as measured by the Boyden chamber assay. This suggests that MCP-1-CCR2 axis may regulate invasiveness via the MAP kinase pathway. Knocking down MCP-1 by shRNA decreased cell invasion in TNBC cell line, BT-549, along with downregulation of key epithelial-to-mesenchymal transition markers, N-cadherin and Vimentin. Recombinant MCP-1 treatment in TNBC MDA-MB-231 cells upregulated genes associated with cytokine signaling. Conclusion : Our study suggests that a high MCP-1 level in TNBC cells may be responsible for increase in cell invasion via the MAP kinase pathway. Thus, MCP-1-mediated pathways could be potential therapeutic targets for the treatment of TNBC and reduce cancer health disparities. Citation Format: Pranabananda Dutta, Kimberly Paico, Yanyuan Wu, Marianna Sarkissyan, Jaydutt Vadgama. Tumor-derived MCP-1 regulates invasiveness in triple-negative breast cancer via the MAP kinase pathway [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B55.","PeriodicalId":146931,"journal":{"name":"Cell, Molecular, and Tumor Biology","volume":"87 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123944284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}