tbuckley/cabot-search huggingface dataset:
Abstract 4862: SORBS1-AHNAK complex regulates metastatic properties of cancer
Authors: Woo-Cheol Cho, Ji-Eun Jang, Ja-Lok Ku
Journal: Cancer Research (2017)

Abstract Purpose: CAP encoded by SORBS1, Vinexin and ArgBP2 is participated in the SoHo family of proteins. The SoHo protein interacts with different signaling molecules and involves with cell migration, and has been implicated in a variety of cellular processes including insulin-stimulated glucose transport. CAP has specific role in the stabilization of adhesion complexes and the consequent effect of cell migration. It is possible that CAP or complex between CAP and other proteins induces change of cancer cell characters. We assumed that SORBS1 has substantial role of cell proliferation, migration and interaction with other subcellular proteins. Methods and materials: To elucidate endogenous role of SORBS1, colorectal cancer cell lines were manipulated by pcDNA, siRNA and shRNA in some colorectal cancer cell lines. Function of SORBS1 as regulator of cancer proliferation was demonstrated by cell cycle assay. And several methods including western blotting, cell migration assay and immunoprecipitation assay were performed for determining role of SORBS1 related other metastatic properties. Conclusion: Colony formation ability and proliferation were induced by SORBS1-overexpression in HT29 cell line. In contrast, transient suppression of SORBS1 inhibits cell proliferation. Moreover, when SORBS1 was constantly suppressed in HCT-116 and SNU-C4 cell line, cell migration was impeded. According to immunoprecipitation data, we chose the AHNAK protein as the convincing candidate protein related with SORBS1. An interaction of SORBS1 and AHNAK was observed in both cytoplasm and nucleus. Expression level of SORBS1 and AHNAK was also negative correlation in extraction of cytoplasm and nucleus. SORBS1 and AHNAK bind each other as form of protein complex, however, AHNAK known as nucleoprotein is abundant in both cytoplasm and nucleus when SORBS1 is suppressed. Consequently, these results indicate that SORBS1 has a key role of cancer cell growth and invasiveness through regulation of AHNAK expression and degradation. Note: This abstract was not presented at the meeting. Citation Format: Woo-Cheol Cho, Ji-Eun Jang, Ja-Lok Ku. SORBS1-AHNAK complex regulates metastatic properties of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4862. doi:10.1158/1538-7445.AM2017-4862
Abstract 3561: UCP2’s tumor-promoting role via regulating lipid signaling and PLCγ -1 activity
Authors: Annapoorna Sreedhar, Yunfeng Zhao
Journal: Cancer Research (2017)

Abstract Mitochondrial abnormalities are long suspected to play important roles in tumor cell differentiation, proliferation and metabolism. Dysfunction of mitochondrial-dependent processes appear to be key features of cancerous cells. Among many such abnormal features of cancerous cells, a mitochondrial uncoupling protein 2 (UCP2) is shown to be up-regulated in various aggressive human cancers. Uncoupling proteins are a family of mitochondrial proteins present in the inner mitochondrial membrane whose physiological role is to decrease membrane potential and reactive oxygen species (ROS) production. UCP2 over-expression recently been proposed as a novel survival mechanism for cancer cells. However, till date, the exact role of UCP2 in cancer remains inconclusive. We recently reported that UCP2 appears to be a key regulator of cell proliferation, cell cycle and cell death during skin tumorigenesis. Using JB6P+ cells that overexpress UCP2, we showed that UCP2 expression correlated closely with cell proliferation and cell transformation. Moreover, inhibition of UCP2, decreased colony formation and 3D culture growth. Since UCP2 is the crucial player in the regulation of reactive oxygen species, and mitochondrial bioenergetics, we wanted to dissect out the role of UCP2 in redox regulation and tumor promotion. Our data demonstrated that UCP2 differentially regulated ROS. UCP2 upregulation, decreased superoxide production, whereas increased hydrogen peroxide production with a concomitant increase in manganese superoxide dismutase (MnSOD) expression and activity. Furthermore, hydrogen peroxide was responsible for induction of lipid peroxidation and PLCγ-1 activation in UCP2 overexpressed cells. Moreover, PLCγ-1 activation enhanced tumorigenecity. Strikingly, pharmacological and siRNA mediated inhibition of PLCγ-1 markedly reduced colony formation and 3D growth in vitro. Lastly, restricting hydrogen peroxide production with hydrogen peroxide scavenger catalase, suppressed lipid peroxidation and dampened PLCγ-1 activity. Taken together, our data suggest that hydrogen peroxide might be the mediator of UCP2’s tumor promoting role, and pharmacological disruption of PLCγ-1, and/or hydrogen peroxide may have clinical utility for UCP2-overexpressed cancers. This research was funded by NCI and Feist-Wellier Cancer Center of LSUHSC-S Citation Format: Annapoorna Sreedhar, Yunfeng Zhao. UCP2’s tumor-promoting role via regulating lipid signaling and PLCγ -1 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3561. doi:10.1158/1538-7445.AM2017-3561
Abstract P240: Mitochondrial Reactive Oxygen Species Regulate the Cardiac Na <sup>+</sup> Channel in Heart Failure
Authors: Man Liu, Hong Liu, Euy-Myoung Jeong, Lianzhi Gu, Samuel C Dudley
Journal: Circulation Research (2011)

Background: Previously, we have shown that elevated intracellular NADH causes a decrease in cardiac Na + current ( I Na ) signaled by an increase in mitochondrial reactive oxygen species (ROS). The decrease in I Na can be ameliorated by NAD + or a mitochondrial specific anti-oxidant, mitoTEMPO. It is known that cardiomyopathy is associated with reduced I Na . Therefore, we tested whether the NADH-mitochondrial ROS pathway was involved in the reduction in I Na in cardiomyopathic mice. Methods: Nonischemic cardiomyopathy was induced in C57BL/6 mice 6 weeks after unilateral nephrectomy, deoxycorticosterone acetate (DOCA) pellet implantation, and salt water substitution. Sham operated mice were used as controls. Ventricular myocytes isolated from mice were utilized for whole-cell patch clamp recording, intracellular NADH/NAD + level measurements, and mitochondrial ROS monitoring with confocal microscopy. Results: Compared to the sham mice, the left ventricular volume was significantly enlarged (105.5 ± 4.4 µL vs. 91.6 ± 4.0 µL, P&lt;0.05), and the ejection fraction was significantly reduced (39.2 ± 1.6% vs. 48.7 ± 1.6%, P&lt;0.05) in DOCA mice. Intracellular NADH level was increased (2.78-fold; P&lt;0.01), and I Na was decreased (62±8%; P&lt;0.01) in myocytes of DOCA mice vs. sham. NAD + (500 μ M) and mitoTEMPO (10 μ M) recovered I Na (90±9% and 103±9% of sham, respectively, P&gt;0.05). Mitochondrial ROS overproduction was observed with DOCA mice myocytes by MitoSOX Red (∼4.8-fold of sham; P&lt;0.01). NAD + and mitoTEMPO decreased ROS in DOCA mice myocytes (∼20±6% of DOCA for both, P&lt;0.01). Conclusions: NADH and mitochondrial ROS were elevated, and I Na was decreased in nonischemic cardiomyopathy. Maneuvers that reduced mitochondrial ROS restored I Na . Since reduced I Na and the subsequent slow conduction velocity are thought to contribute to arrhythmic risk in this condition, NAD + and mitochondrial anti-oxidants may have anti-arrhythmic activity in cardiomyopathy.
Numb−/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling
Authors: Yanjing Guo, Kai Zhang, Chaping Cheng, Zhongzhong Ji, Xue Wang, Minglei Wang, Mingliang Chu, Dean G. Tang, Helen He Zhu, Wei-Qiang Gao
Journal: Clinical Cancer Research (2017)

Purpose: To elucidate the role and molecular mechanism of Numb in prostate cancer and the functional contribution of Numb-/low prostate cancer cells in castration resistance.Experimental Design: The expression of Numb was assessed using multiple Oncomine datasets and prostate cancer tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human prostate cancer cell lines were investigated in vitro and in vivo In addition, we developed a reliable approach to distinguish between prostate cancer cell populations with a high or low endogenous expression of Numb protein using a Numb promoter-based lentiviral reporter system. The difference between Numb-/low and Numbhigh prostate cancer cells in the response to androgen-deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting, and quantitative real-time PCR.Results: We show here that Numb was downregulated and negatively correlated with prostate cancer advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and castration-resistant prostate cancer development by suppressing Notch and Hedgehog signaling. Using a Numb promoter-based lentiviral reporter system, we were able to distinguish Numb-/low prostate cancer cells from Numbhigh cells. Numb-/low prostate cancer cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb-/low cells in response to ADT.Conclusions: Numb-/low enriches a castration-resistant prostate cancer cell subpopulation that is associated with unregulated Notch and Hedgehog signaling. Clin Cancer Res; 23(21); 6744-56. ©2017 AACR.
Abstract 4987: ASS1 downregulation facilitates cancer cell survival in acidic environment
Authors: Ayelet Erez, Alon Silberman, Adi Jacob, Shiran Limanovich, Odeya Boukobza1, Erez Persi, Rom Keshet, Alona Sarver, Joo Sang Lee, Alexander Brandis, Keren Bahar Halpern, Raya Eilam, Ben Pode, Yair Anikster, Igor Ulitsky, Sandesh Nagamani, Eytan Ruppin
Journal: Cancer Research (2017)

Abstract ”pH gradient reversal”, namely the alkalinization of intracellular pH (pHi) and acidification of extracellular pH (pHe), is a unique phenotype of cancer cells which enable cancer survival, migration and invasion. Hence, not surprisingly, pH gradient reversal is emerging as a new hallmark of cancer. Argininosuccinate synthase, ASS1, is a urea cycle enzyme found to be downregulated by methylation in multiple different types of cancers in correlation with increased metastasis and poor prognosis. We recently showed that ASS1 downregulation increases proliferation by channeling aspartate towards pyrimidine synthesis by CAD. We now show that under hypoxia and acidic environments, ASS1 is downregulated together with CAD by HIF1α as part of an essential network necessary for cancer cells’ survival, invasion and migration. Similar to germline deficiency of ASS1 which increases the levels of glutamine and ammonia, ASS1 downregulation by HIF1αenables the cancer cells to increase glutamine levels allowing its utilization for glutathione and importantly, for preservation of alkali pHi by elevating ammonia levels and buffering the acidity caused by cancers’ enhanced glycolysis and the consequent increase in lactic acid. Moreover, cancer cells which express ASS1 when grown in culture, downregulate its expression in hypoxic regions when grown in vivo, suggesting that these cancers might also be sensitive to drugs previously utilized only in ASS1 deficient cancers. Finally, we show that treating cancers with ASS1 deficiency with ammonia scavengers as given to ASS1 deficient patients, increases apoptosis and restricts migration, and is hence beneficial therapeutically. In summary, ASS1 downregulation is regulated differently at altered carcinogenic states, promoting proliferation as well as cancer survival and metastasis. Citation Format: Ayelet Erez, Alon Silberman, Adi Jacob, Shiran Limanovich, Odeya Boukobza1, Erez Persi, Rom Keshet, Alona Sarver, Joo Sang Lee, Alexander Brandis, Keren Bahar Halpern, Raya Eilam, Ben Pode, Yair Anikster, Igor Ulitsky, Sandesh Nagamani, Eytan Ruppin. ASS1 downregulation facilitates cancer cell survival in acidic environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4987. doi:10.1158/1538-7445.AM2017-4987
Associations Between Sexual Orientation and Overall and Site-Specific Diagnosis of Cancer: Evidence From Two National Patient Surveys in England
Authors: Catherine L. Saunders, Catherine Meads, Gary A. Abel, Georgios Lyratzopoulos
Journal: Journal of Clinical Oncology (2017)

Purpose To address gaps in evidence on the risk of cancer in people from sexual minorities. Patients and Methods We used data from 796,594 population-based English General Practice Patient Survey responders to explore the prevalence of self-reported diagnoses of cancer in the last 5 years among sexual minorities compared with heterosexual women and men. We analyzed data from 249,010 hospital-based English Cancer Patient Experience Survey responders with sexual orientation as a binary outcome, and International Classification of Diseases, Tenth, Revision, diagnosis as covariate—38 different common and rarer cancers, with breast and prostate cancer as baseline categories for women and men, respectively—to examine whether people from sexual minorities are over- or under-represented among different cancer sites. For both analyses, we used logistic regression, stratified by sex and adjusted for age. Results A diagnosis of cancer in the past 5 years was more commonly reported by male General Practice Patient Survey responders who endorsed gay or bisexual orientation compared with heterosexual men (odds ratio [OR], 1.31; 95% CI, 1.15 to 1.49; P &lt; .001) without evidence of a difference between lesbian or bisexual compared with heterosexual women (OR, 1.14; 95% CI, 0.94 to 1.37; P = .19). For most common and rarer cancer sites (30 of 33 in women, 28 of 32 in men), the odds of specific cancer site diagnosis among Cancer Patient Experience Survey respondents seemed to be independent of sexual orientation; however, there were notable differences in infection-related (HIV and human papillomavirus [HPV]) cancers. Gay or bisexual men were over-represented among men with Kaposi’s sarcoma (OR, 48.2; 95% CI, 22.0 to 105.6), anal (OR, 15.5; 95% CI, 11.0 to 21.9), and penile cancer (OR, 1.8; 95% CI, 0.9 to 3.7). Lesbian or bisexual women were over-represented among women with oropharyngeal cancer (OR, 3.2; 95% CI, 1.7 to 6.0). Conclusion Large-scale evidence indicates that the distribution of cancer sites does not vary substantially by sexual orientation, with the exception of some HPV- and HIV-associated cancers. These findings highlight the importance of HPV vaccination in heterosexual and sexual minority populations.
Abstract 263: Epidemiology of primary lung cancer and its trend northeast of Iran during 1985-2012
Authors: Maryam Salehi, Pardis Shojaee, Soodabeh Shahidsales, Seyed Amir Aledavood, Mehdi Seilaniantoosi, Golboo Goshayeshi, Fahimeh Khoshroo
Journal: Cancer Research (2017)

Abstract Introduction: In this study we investigated epidemiology and trends of primary lung cancers in northeast of Iran during 1985-2012. Methods: In this cross-sectional study records of primary lung cancers from 1985 to 2012 in Mashhad, northeast of Iran, were investigated. Data were obtained from the referral oncologic hospital and private radiation oncology clinic. To study trends, the duration of study was categorized into three periods: 1985-1995, 1995-2005 and 2005-2012. Statistically significant level was considered &amp;lt;0.05. Results: Of 939 cases with mean age of 60.57 (±12.31) years, 660(70.3%) were male. Male to female ratio was 2.36. Mean age was 61.47±12.01 years for males and 58.45±12.75 for females (p=0.001). Mean age at diagnosis and rate of smokers was unchanged in three intervals (table 1). Time period1985-19951995-20052005-20012P valueAge(years)60.67±11.7460.57±12.2460.49±12.940.98Gender:Male167(78.4)330(68.6)163(66.5)0.01female46(21.6)151(31.4)82(33.5Male to female ratio3.632.181.99Smoking history:Yes69(76.7)211(67.8)100(65)0.15no21(23.3)100(32.2)54(35)Smokers:Male59(85.5)159(75.4)74(74)0.16Female10(14.5)52(24.6)26(26)Male-to-female ratio of smokers5.93.062.84 Squamous cell carcinoma with relative frequency of 44.2% was the most frequent pathologic subtype in total population followed by adenocarcinoma (18.2%), Small Cell Lung cancer (16.8%), large Cell carcinoma (1.3%) and other subtypes (19.5%). Relative frequency of pathologic subtypes had significant changes in three intervals (p &amp;lt;0.001). Relative frequency of adenocarcinoma and large cell carcinoma were increasing while it was decreasing for SCC and SCLCs during three recent decades. There was statistically significant difference in mean age at diagnosis (p&amp;lt;0.001), rate of smokers (p&amp;lt;0.001) and male to female ratio (p=0.01) between four leading pathologic subtypes. Mean age at diagnosis (55.92±12.90 years), male to female ratio (1.69), and rate of smokers (46.8%) were lowest in adenocarcinomas. Conclusion: Similar to universal picture, adenocarcinoma showed increasing rates during recent three decades with higher prevalence among younger aged patients, women and nonsmokers. These trends are indicative of changes in exposures and smoking habits and reveal the need for regional studies in this context. Citation Format: Maryam Salehi, Pardis Shojaee, Soodabeh Shahidsales, Seyed Amir Aledavood, Mehdi Seilaniantoosi, Golboo Goshayeshi, Fahimeh Khoshroo. Epidemiology of primary lung cancer and its trend northeast of Iran during 1985-2012 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 263. doi:10.1158/1538-7445.AM2017-263
Abstract 3742: Exposure burden for patients during an experimental study using a dual-energy contrast-enhanced spectral mammography
Authors: Kamila Rawojc, Kamil Kisielewicz, Anna Dziecichowicz, Monika Tomaszuk, Anna Cepiga, Jankowska Anna, Cieśla Izabela, Najberg Dominika, Luczynska Elzbieta, Bartosz Kieltyka
Journal: Cancer Research (2017)

Abstract Mammography provides early micro-calcification recognition, that is important for further breast cancer (BC) diagnosis. Imaging choice for BC detection is X-ray mammography (MG) with the use of high-resolution digital modality combined with iodinated contrast agents. However, a conventional MG has some sensitivity limitations, especially in patients with densely treated breasts. Moreover, MG contributes radiation risk for BC that is correlated with an exposure to ionizing radiation. Patients, for whom MG study does not give a clear interpretation are often further diagnosed by contrast-enhanced breast MRI, the most sensitive BC detection technique. Alternatively, it is limited by higher costs, lower availability and increased false positives. Dual-energy contrast-enhanced spectral mammography (CESM) is a new method applied in BC that enables accurate detection of malignant breast lesions similar to breast MRI. The aim of this study was to compare the usefulness of CESM versus MG in BC detection. Additionally, doses given to the BC patients during imaging were compared. In this study, 250 consecutive women (144 MG vs. 105 CESM), that were screened using mammography between 2011 and 2014 were retrospectively enrolled in the study. The comparison of entrance surface air kerma and mean glandular dose values for both options were recorded, respectively and analyzed using different statistical and retrospective approach. Results of presented study showed that CESM might be a new diagnostic tool allowing an accurate detection of BC lesions, giving results similar to those received from magnetic resonance imaging. A good agreement found between sensitivity of the method and tumour diameters measurements based on CESM, supports this tool as a potential replacement for breast MRI in the preoperative evaluation of BC patients. However, a radiation burden for patients might be significantly higher than that for a standard full-field digital mammography procedure. In summary, each method has its own benefits with respect to specific applications that are further discussed in the study. Citation Format: Kamila Rawojc, Kamil Kisielewicz, Anna Dziecichowicz, Monika Tomaszuk, Anna Cepiga, Jankowska Anna, Cieśla Izabela, Najberg Dominika, Luczynska Elzbieta, Bartosz Kieltyka. Exposure burden for patients during an experimental study using a dual-energy contrast-enhanced spectral mammography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3742. doi:10.1158/1538-7445.AM2017-3742
Abstract 4525: Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance
Authors: Noelle L. Cutter, Tyler Walther, Kimberly H. Doyle, Ryan Frank
Journal: Cancer Research (2017)

Abstract Hypoxia-inducible factor 1 (HIF-1) is a basic helix-loop-helix transcription factor that when induced regulates the expression of many genes involved in cytoprotective stimuli, which attenuates apoptosis and improves survival.. Increased expression of HIF-1α gene (HIF1A) has been found in several carcinomas, including ovarian cancer. Ovarian cancers are generally refractory to platinum-based chemotherapy. Despite the large number of studies, molecular events that govern the emergence of aggressive therapy-resistant cells after chemotherapy are poorly defined. Genomic instabilities, such as copy number variation(CNV), may play an important role in chemoresistance and have been implicated in many complex diseases, like cancer.. We analyzed CNV data that is publically available through the Cancer Genome Atlas and others. Of particular interest was the transcription factor HIF1A which plays an integral role in oxidative stress response such as those induced by chemotherapy reagents. The present study provides evidence for the rare escape of tumor cells from drug-induced cell death by entering a non-cycling senescent state. We report the adaptive response of human ovarian surface epithelium cells to CoCl2, a chemical hypoxia-mimicking agent resulting in a senescent-like state of chemoresistant cells. The effect of the treatment was evaluated on CNV of HIF-1α gene expression, cell proliferation, survival, and tumor invasiveness. We show here that CNV duplication events of HIF1α results in an oxidative stress response in cells leading to chemoresistance through the induction of cellular senescence. Understanding the molecular events associated with chemoresistance will ultimately lead to better patient treatment and outcomes. Note: This abstract was not presented at the meeting. Citation Format: Noelle L. Cutter, Tyler Walther, Kimberly H. Doyle, Ryan Frank. Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4525. doi:10.1158/1538-7445.AM2017-4525