bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5150: Identification of higher mRNA expression of both Kitenin and ErbB4 CYT-2 isoform as a molecular marker for the prediction of transition from colon adenoma to carcinoma
Authors: Bae Jeong A , Sun Eun Gene , Ko Yoo-Seung , Choi Hui Jeong , Bae Woo-Kyun , Cho Sang-Hee , Chung Ik Joo , Moon Kyung-Sub , Yu Young-Hyun , Ha Hyung-Ho , Kim Hangun , Kim Kyung Keun 
Published: July 2016

Abstract
Purpose: The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer (CRC) cells and we recently identified a novel EGFR-independent oncogenic signal of EGF that works under co-expressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contributes to further progression of intestinal adenoma following APC loss.
Results & Discussion: The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven elevated KITENIN induced increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes, compared with those of non-transgenic mice. Among the 4 ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells co-expressing KITENIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of ErbB4 CYT-2 isoform mRNA as well as increased EGFR expression were observed in intestinal adenoma of APCmin/+ mice making the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APCmin/+ mice, intestinal tumor tissues in the crossed mice showed the characteristics of early stage invading adenocarcinoma. In CRC patients, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no differences in tumoral expression between the stages, and a positive correlation exists between KITENIN and ErbB4-CYT-2 mRNA expression. Thus, elevated expression of KITENIN and ErbB4-CYT-2 is newly identified as a factor that promotes the transition of colon adenoma to adenocarcinoma within an APC-loss-associated tumor microenvironment.
Conclusion: Higher mRNA expression of both KITENIN and ErbB4-CYT-2 in colon adenoma tissues can be used as a molecular marker of the possible development of malignant transformation.
Citation Format: Jeong A Bae, Eun Gene Sun, Yoo-Seung Ko, Hui Jeong Choi, Woo-Kyun Bae, Sang-Hee Cho, Ik Joo Chung, Kyung-Sub Moon, Young-Hyun Yu, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim. Identification of higher mRNA expression of both Kitenin and ErbB4 CYT-2 isoform as a molecular marker for the prediction of transition from colon adenoma to carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5150.
Abstract 5152: Inhibition of TLR/IRAK pathway in hepatocellular carcinoma augmented therapeutic responses
Authors: Cheng Yik Ling Bowie , Ng Oi Lin Irene , Lee. Kin Wah Terence 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC) is the second most lethal cancer worldwide. Frequent relapse and drug resistance accounts for the poor prognosis, which could be attributed by the presence of cancer stem cells (CSCs), a subpopulation that harbor the properties of self-renewal, clonal tumor initiation and long-term repopulation capacity. Toll like receptors (TLRs) are widely expressed on immune cells and TLR/Interleukin-1 receptor associated kinase (IRAK) pathway was originally best known for their role in the induction of innate immune responses, but it was recently found to be frequently up-regulated in various cancers, although its role in cancer development remains largely unexplored.
By RNA sequencing analysis of 16 pairs of HCC clinical samples, we found IRAK1 to be significantly overexpressed in HCC among all members of IRAK family. By quantitative PCR and western blot analyses, overexpression of IRAK1 at both mRNA and protein level was confirmed, which correlated with advanced tumor stage (p = 0.04). By lentiviral-based over-expression and knockdown approaches, we demonstrated that IRAK1 promoted cell proliferation and invasiveness. Interestingly, IRAK1 regulated CSC properties including tumorigenicity, self-renewal, drug resistance and expression of liver CSC markers including CD24 and CD47. To further examine the therapeutic potentials of targeting IRAK1 in HCC, we treated HCC cells with IRAK1/4 inhibitor. Suppression of IRAK1 at 10μM not only consistently inhibited CSC properties, but also augmented the effect of sorafenib, a molecularly targeted drug for treatment of advanced HCC. The cancer-promoting and drug desensitization effect of IRAK1 could be partly explained by activation of NF-κB signaling pathway as well as down-regulation of apoptotic cascade.
Conclusion:
Overexpression of IRAK1 in HCC promotes cancer progression by enhancing proliferation and invasiveness; Importantly, IRAK1 may promote cancer stemness and confers resistance to sorafenib. All in all, targeting IRAK1 with specific small molecule inhibitor alone or in combination with other drugs may be a novel therapeutic regimen for treatment of HCC.
Citation Format: Yik Ling Bowie Cheng, Oi Lin Irene Ng, Kin Wah Terence Lee. Inhibition of TLR/IRAK pathway in hepatocellular carcinoma augmented therapeutic responses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5152.
Abstract 5158: The change of EZH2 expression in development of colorectal cancer from adenoma
Authors: Ohuchi Mayuko , Nakamoto Yasuo , Tokunaga Ryuma , Nakamura Kenichi , Kosumi Keisuke , Harada Kazuto , Shigaki Hironobu , Kurashige Junji , Iwatsuki Masaaki , Baba Yoshifumi , Miyamoto Yuji , Yoshida Naoya , Baba Hideo 
Published: July 2016

Abstract
[Background]Colorectal cancer has been revealed to develop from adenoma through mutation and deletion of various genes such as FAP, KRAS, DCC and p53 in the process called adenoma-carcinoma sequence. Furthermore, proteins of the polycomb repressive complex 2 (PRC2) function as transcriptional repressors by trimethylating histone H3 at lysine 27, and this complex's activity is essential for cell proliferation and differentiation. The histone methyltransferase enhancer zeste homolog 2 (EZH2), a key member of PRC2, is associated with transcriptional repression of tumor suppressor gene. In our previous study, EZH2 expression was reported to increase as pathology worsened in pancreatic IPMN. Thus EZH2 expression was hypothesized to increase in the adenoma-carcinoma sequence as well.[Purpose]The purpose of this study was to investigate the change of EZH2 expression in progressing colorectal cancer. [Materials and Methods]63 patients with colorectal adenoma, 24 patients with carcinoma in adenoma and 14 patients with colorectal carcinoma who underwent surgical or endoscopic resection were enrolled in this study. The normal lesions of the clinical specimens were also examined. We evaluated the association between EZH2 expression, pathology and expression of tumor suppressor gene. Immunohistochemistry of EZH2, Ki-67, p21, p27 and p16 was performed.[Results]The Ki-67 expression increased parallel to the worsening of pathological findings (p = 0.009), and EZH2 expression showed a significantly positive association with Ki-67 expression (p = 0.02). There was a significant increase of EZH2 expression between normal and colorectal adenoma and carcinoma in adenoma. However, no significance between carcinoma in adenoma and colorectal cancer in EZH2 expression could be identified. Conversely, p21 expression decreased significantly between normal and adenoma lesion; however, p16 and p27 expression showed no major change. [Conclusion]EZH2 expression considerately increased parallel to pathological worsening and p21 expression showed a decrease between normal and colorectal adenoma. Thus EZH2 can contribute to development of colorectal cancer from adenoma via p21 suppression.
Citation Format: Mayuko Ohuchi, Yasuo Nakamoto, Ryuma Tokunaga, Kenichi Nakamura, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Junji Kurashige, Masaaki Iwatsuki, Yoshifumi Baba, Yuji Miyamoto, Naoya Yoshida, Hideo Baba. The change of EZH2 expression in development of colorectal cancer from adenoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5158.
Abstract 5159: Smad7 knockdown in colon cancer cells activates protein kinase RNA-associated eIF2α pathway thereby leading to cell death
Authors: De Simone Veronica , Bevivino Gerolamo , Sedda Silvia , Izzo Roberta , Fantini Massimo Claudio , Monteleone Giovanni 
Published: July 2016

Abstract
Background. Up-regulation of Smad7, an inhibitor of TGF-β1, occurs in sporadic colorectal cancer (CRC). Knockdown of Smad7 with a specific antisense oligonucleotide (AS) leads to activation of eIF2α, an attenuator of protein synthesis, and arrest of CRC cells in the S phase of the cell cycle with the downstream effect of inducing cell death.
Aim. To investigate the mechanisms by which Smad7 knockdown activates eIF2α.
Methods. Phosphorylation of eIF2α was evaluated in CRC cell lines (i.e. HCT116 and DLD-1) either untreated or treated with Smad7 sense (S) or AS by Western blotting (WB) and immunofluorescence (IF). Expression of ATF4 and CHOP, two downstream targets of EIF2α, were evaluated by IF and activation of PKR, GCN2 and PERK, up-stream kinases that induce eIF2α phosphorylation, was assessed by WB. Wild type or PKR-deficient CRC cells treated with Smad7 AS were monitored for eIF2α activation and induction of death. Finally, we assessed whether enhanced phosphorylation of eIF2α seen in cells treated with Smad7 AS was also associated with reduced interaction between eIF2α and PP1, a phosphatase that normally dephosphorylates eIF2α.
Results. Smad7 knockdown increased ATF4 and CHOP expression thus confirming previous data showing activation of eIF2α phosphorylation in CRC cells treated with Smad7 AS. Among kinases that induce eIF2α phosphorylation, only PKR was activated by Smad7 knockdown. Consistently, silencing of PKR reduced but did not abolish Smad7 AS-induced eIF2α phosphorylation and cell death, thus suggesting the existence of further mechanisms that control eIF2α phosphorylation in Smad7-deficient cells. Indeed, in CRC cells, Smad7 interacted with PP1 and Smad7 knockdown reduced association of PP1 with eIF2α.
Conclusions
Data show that Smad7 is involved in CRC cell survival and suggest that Smad7 is a valid target for therapeutic intervention in CRC.
Citation Format: Veronica De Simone, Gerolamo Bevivino, Silvia Sedda, Roberta Izzo, Massimo Claudio Fantini, Giovanni Monteleone. Smad7 knockdown in colon cancer cells activates protein kinase RNA-associated eIF2α pathway thereby leading to cell death. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5159.
Abstract 516: The mechanism associated with radio-resistant renal cell carcinoma and its targeting strategy
Authors: Yun Eun-Jin , Lin Chun-Jung , Saha Debabrata , Hsieh Jer-Tsong 
Published: July 2016

Abstract
Introduction and Purpose: Although ionizing radiation (IR) represents an effective regimen for most solid tumors, renal cell carcinoma (RCC) is known to be highly radio-resistant and the underlying mechanisms associated with IR-resistance remained elusive. In this study, we unveiled the factors associated with IR-resistance and the potential targeting strategy.
Experimental procedures: Several RCC sublines were generated with different genetic manipulation and cells were irradiated with different doses and the surviving fractions were evaluated in 7 days. To investigate the underlying mechanism, various biochemical and molecular biologic methods, such as quantitative real-time PCR, mass-spectroscopy (MS), immunoprecipitation (IP), western blot, and ELISA were performed.
Results: DAB2IP (DOC-2/DAB2 interactive protein) known as a tumor suppressor that functions as a scaffold protein modulating many signal pathways associated cell growth/survival, apoptosis/autophage, and cell migration/invasiveness. In RCC, the status of DAB2IP has not been characterized. We found DAB2IP was frequently lost in RCC; more than 50% in every subtype of RCC. We observed that DAB2IP-deficient RCC cells exhibited IR-resistance whereas re-introduction of DAB2IP could sensitize RCC cells to IR. From MS and IP, it appeared that DAB2IP could directly interact with poly (ADP-ribose) polymerase-1 (PARP-1). In the presence of DAB2IP, PARP-1 activities were suppressed because DAB2IP was able to induce PARP-1 protein degradation via unique proteasome pathway. Since PARP-1 is commonly involved in many cellular functions such as DNA damage repair or transcription modulation, which is also considered as a therapeutic target particularly IR therapy. In this study, elevated PARP-1 led to rapid DNA repairing and IR resistance in DAB2IP-expressing RCC cells. In contrast, by knocking-down PARP-1 in DAB2IP-deficient RCC cells can sensitize cells to IR, suggesting that PARP-1 inhibitors can be a potential radio-sensitizer.
Conclusion: In summary, this study demonstrates a new functional role of DAB2IP in IR-resistant RCC cells via modulating PARP-1 expression and activities. Therefore, targeting PARP-1 by small molecular inhibitor or gene therapy becomes a potential therapeutic strategy to overcome IR resistant RCC.
Citation Format: Eun-Jin Yun, Chun-Jung Lin, Debabrata Saha, Jer-Tsong Hsieh. The mechanism associated with radio-resistant renal cell carcinoma and its targeting strategy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 516.
Abstract 5161: Development of cutaneous basal cell carcinomas from cutaneous actinic keratoses
Authors: Lambert W Clark , Gagna Claude E. , Lambert Muriel W. 
Published: July 2016

Abstract
Actinic keratoses (AKs) are extremely common proliferations of epidermal keratinocytes which show cytological atypia and impaired ability to mature as the cells that comprise them migrate from the basal layer of the epidermis to higher levels of the epidermis. A small percentage of AKs are well known to progress to cutaneous squamous cell carcinomas (SCCs). However, progression of AKs to cutaneous basal cell carcinomas (BCCs) has not been convincingly documented despite several attempts, even though BCCs are significantly more common than SCCs in the general US and European populations. Documented cases have been dismissed as actinic keratoses that have simply occurred superimposed upon basal cell carcinomas due to chance occurrence of two common sun induced skin lesions at the same sites.
In a university based referral dermatopathology service, one of us (WCL) observed 21 cases of AKs progressing to BCCs during a 29 year period (January 1, 1985 to December 31, 2013) of continuous observation in which 115,898 cases of AKs, 10,188 cases of BCCs and 4,809 cases of SCCs were diagnosed. Only cases in which a continuous progression of cells from those showing changes typical of AKs to those showing changes typical of BCCs was observed were included. During the same interval 308 cases of AKs progressing to SCCs were diagnosed. To further test the hypothesis that AKs can progress to BCCs, cases of AKs that progressed to BCCs were further examined to determine those in which neither the AK nor the BCC occupied the entire skin surface (i.e., length of the epidermal basement membrane) present in the specimen. Of the 21 cases, 13 met this criterion. All were shave biopsies of sun damaged skin. For each biopsy, the proportion of the surface covered by the AK, the proportion occupied by the BCC, and the proportion of the surface overlapped by both lesions were measured and the proportion of overlap was compared to the proportion of overlap expected due to chance. Statistical analysis showed that the observed overlap exceeded the expected overlap by 32 per cent with p &lt; 0.05. We conclude that progression of AKs to BCCs, while not as common as progression of AKs to SCCs, does occur in a small proportion of cases.
Citation Format: W Clark Lambert, Claude E. Gagna, Muriel W. Lambert. Development of cutaneous basal cell carcinomas from cutaneous actinic keratoses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5161.
Abstract 5162: Id1 is an oncogenic target of RNA binding protein HuR in gastric cancer
Authors: Han Shuang , Wu Xiaoqing , Guo Yuxiao , Zhang Jing , Gu Xuan , Marquez Rebecca T. , Aube Jeffrey , Xu Liang 
Published: July 2016

Abstract
Hu antigen R (HuR), a ubiquitous RNA-binding protein (RBP), has been shown to be overexpressed in gastric cancer. Cytoplasmic HuR is reported to be associated with high stage, distant metastases and unresectability. HuR efficiently regulates cancer-related gene expression by binding to AU- and U-rich sequences (ARE) in the 3’ and 5’-untranslated region (UTR) of mRNAs. Id1 (Inhibitor of DNA binding) is a putative oncogene that we previously found was upregulated in gastric cancer and associated with poor prognosis. Id1 mRNA contains several putative HuR ARE sites. Our goal is to determine the impact of HuR on Id1 expression. We first confirmed Id1 is a HuR target by Ribonucleoprotein Immunoprecipitation (RNP-IP) in gastric cancer cells. Then, we found KH-3, a potent and specific inhibitor of HuR, inhibited Id1 mRNA and protein expression. The proliferative and invasive capabilities of the gastric cancer cells were also inhibited by KH-3. We conclude that Id1 is a target of RNA-binding protein HuR in gastric cancer. HuR specific inhibitor, KH-3, may be a promising therapeutic agent in treating HuR/Id1 high gastric cancers.
Citation Format: Shuang Han, Xiaoqing Wu, Yuxiao Guo, Jing Zhang, Xuan Gu, Rebecca T. Marquez, Jeffrey Aube, Liang Xu. Id1 is an oncogenic target of RNA binding protein HuR in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5162.
Abstract 5176: Orthotopic syngeneic tumor models for preclinical evaluation of cancer immunotherapy strategies
Authors: Zhang Juan , Guo Sheng , Wang Zhensheng , Li zhongliang , Qiao Meng , Shi Qian 
Published: July 2016

Abstract
Background: The recent successes of cancer immunotherapies have stimulated interest in the potential application of these approaches in many solid and hematologic tumors. Syngeneic tumor models have been widely used in cancer immunotherapy assessment. However, most of these experimental models were established as subcutaneous models, while there may be significant difference in immune microenvironment comparing orthotopic vs. subcutaneous tumors. In addition, drug delivery and metabolism are different in orthotopic tumors vs. subcutaneous tumors. To address this unmet need, we set out to validate a panel of orthotopic syngeneic models for anti-cancer therapeutics (mainly immunotherapeutics) evaluation.
Results: A large collection of orthotopic syngeneic models covering breast cancer, liver cancer and various hematological cancers were established in immunocompetent mice. Survival curves were established and the responsiveness to anti-PD1, anti-PDL1 and anti-CTLA4 antibodies were evaluated in the orthotopic models. Orthotopic liver tumors were monitored with ultrasound imaging to obtain longitudinal growth curves. The correlation in drug efficacy between the orthotopic model and its subcutaneous counterpart was analyzed. The role of NK cells in the development of a panel of systemic hematological tumor models was investigated with NK depleting antibodies.
Conclusion: Despite the obvious difficulties, orthotopic syngeneic models represent closer model systems to human diseases and may be a valuable tool to the evaluation of cancer immunotherapies and their combination strategies.
Citation Format: Juan Zhang, Sheng Guo, Zhensheng Wang, zhongliang Li, Meng Qiao, Qian Shi. Orthotopic syngeneic tumor models for preclinical evaluation of cancer immunotherapy strategies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5176.
Abstract 5177: RNAseq and FACS profiling of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy
Authors: Zhang Lan , Zhang Juan , Guo Sheng , Qian Wubin , Wang Zhensheng , Shi Qian 
Published: July 2016

Abstract
Background: Syngeneic tumor models have long been used in cancer research. Recently, the clinical success of anti-CTLA4 and anti-PD1 antibodies resulted in increased interests in using syngeneic models to evaluate cancer immunotherapeutics. Furthermore, as researchers discovered chemo, radio and targeted therapies of cancer may interact or change tumor immune environment, they are looking for suitable models that may evaluate the combination of those therapies. More importantly, in the clinic it is still unknown why some patients respond to certain immunotherapies while others do not. We set out to utilize syngenetic models to address those questions.
Material and methods: Syngeneic cell line models were used to evaluate anti-PD1, PD-L1 and CTLA4 antibodies efficacies. 13 tumors from different syngeneic models were collected before the treatment for RNAseq analysis. Tumors were also collected after treatment for immune cell analysis with FACS for PD response. Biomarkers were analyzed with the RNAseq data to predict treatment response to different immune checkpoint inhibitors.
Results: Crown has established the largest collection of syngeneic models with well characterized immunotherapy data. Those models have a diverse response to anti-PD1, PD-L1 and CTLA4 antibodies, ranging from close to 100% inhibition to inducing tumor growth upon antibody treatment. Mostly recently, we have generated detailed maps of the expressional and mutational profiles of those models. Mutational analysis indicated a number of syngeneic models harbor mutations that may be useful for combination studies of targeted and immuno-therapy. Chemo and targeted therapy in combination with immunotherapy in syngeneic models suggested potential strategies that may be successful in the clinic. Analysis of RNAseq and FACS analysis data indicated markers that may be useful to predict immunotherapy response.
Conclusions: These data will enable selection of models for chemo or targeted therapies in combination with immunotherapy. In addition, predictive biomarkers obtained from the analysis may be useful in understanding patient response in the clinic.
Citation Format: Lan Zhang, Juan Zhang, Sheng Guo, Wubin Qian, Zhensheng Wang, Qian Shi. RNAseq and FACS profiling of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5177.