bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5194: Pim2 is required for maintaining Multiple Myeloma cell proliferation through modulating mTORC1 pathway.
Authors: Lu Jing , Zavorotinskaya Tatiana , Dai Yumin , Niu Xiaohong , Castillo Joseph , Sim Janet , Yu Jianjun , Shannon Kevin , Garcia Pablo
Published: August 2014

Multiple Myeloma (MM) is the second most common hematological malignancy. Despite the advances of therapeutic regimens over the last decade, nearly all patients eventually relapse, highlighting the need for additional therapeutic agents. Pim kinases, a family of serine/threonine kinase, are reported to be oncogenic and required for the maintenance of hematological malignancies. Here, consistent with previous reports, we show that Pim2 kinase expression is most highly elevated in MM. Importantly, shRNA knockdown of Pim2 leads to a significant inhibition of MM cell growth, suggesting that Pim2 is critical in maintaining MM malignancy. We developed a potent and specific small molecule inhibitor for the Pim kinases. Inhibition of Pim2 by this molecule suppresses

MM cell growth. We find that Pim inhibitor treatment results in the suppression of cell proliferation, but not induction of apoptosis, in all MM cell lines tested. Further, we identified mTORC1 signaling, which is critical for cell proliferation, as significantly repressed by Pim2 inhibition. The two major mTORC1 downstream effectors: P70S6K and 4EBP1 are rapidly dephosphorylated upon Pim inhibitor treatment of MM cells. We are currently investigating the potential signaling modules that may mediate Pim2’s regulation on mTORC1 pathway. Taken together, our findings strongly support

Pim2 as a promising therapeutic target in MM, given its distinct expression in

MM and essential role in maintaining proliferation.

Citation Format: Jing Lu, Tatiana Zavorotinskaya, Yumin Dai, Xiaohong Niu, Joseph Castillo, Janet Sim, Jianjun Yu, Kevin Shannon, Pablo Garcia. Pim2 is required for maintaining Multiple Myeloma cell proliferation through modulating mTORC1 pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5194. doi:10.1158/1538-7445.AM2013-5194
Abstract 5195: Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma.
Authors: Sabbisetti Venkata , Bhatt Rupal , Ramadesikan Swetha , Bonventre Joseph
Published: August 2014

Background. Renal cell carcinoma (RCC) is characterized by lack of early warning signs, diverse clinical manifestations, absence of a reliable diagnostic and predictive biomarker, and resistance to targeted therapy. Thus, novel approaches for diagnosis, management and treatment of RCC are urgently needed. Kidney Injury Molecule-1 (KIM-1) is not expressed in normal kidney tissues but markedly up-regulated in dedifferentiated proximal tubular epithelial cells following renal injury. We demonstrated that KIM-1 is expressed ubiquitoulsy by both primary and metastatic lesions of clear cell and papillary renal cell carcinoma, while barely detectable in other subtypes of RCC. Additionally, the ectodomain of KIM-1 is cleaved by matrix metalloproteinases and sheds into the surrounding milieu.

Methods. KIM-1 was stably transfected in immortalized renal tubular epithelial cells (LLC-PK1, gain-of-function) and KIM-1 was downmodulated in RCC cell lines (loss-of-function) using a siRNA lentiviral approach. KIM-1 function was assessed using these two systems.

Results. Stable expression of KIM-1 in non-malignant renal epithelial cells increased cell proliferation, migration and invasion potential, induced anchorage independent growth, and increased the secretion of tumor promoting and angiogenic factors including VEGF, Ang2, TGF beta and IL-6 (PK1-KIM-1); while depletion of KIM-1 in RCC cells led to G1 cell cycle arrest phase and senescence. Recently, we and others have demonstrated that KIM-1 is a phosphatildyl serine receptor and the expression of KIM-1 converts a normal epithelial cell into a “semi professional phagocyte” and facilitates the removal of apoptotic and necrotic cells by recognizing phosphotidyl serine (PS) on their cell surface. Our data suggests that during this process, tumor epithelial cells undergo reprogramming and secrete and activate cytokines involved in cell survival and angiogenesis programs.

Conclusions. The present study shows that KIM-1-expression promotes tumorigenesis primarily by two distinct mechanisms: i) by directly conferring oncogenic properties to renal epithelial cells; ii) by resulting in production of a variety of chemokines and cytokines that support tumor progression and angiogenesis. We believe that our findings can significantly contribute to the development of novel therapeutic apporaches and in the advancement of management strategies in RCC and help reduce associated mortality and morbidity.

Citation Format: Venkata Sabbisetti, Rupal Bhatt, Swetha Ramadesikan, Joseph Bonventre. Kidney injury molecule-1: a novel therapeutic target in renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5195. doi:10.1158/1538-7445.AM2013-5195

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5201: Elucidating distinct roles for NF1 in melanomagenesis.
Authors: Maertens Ophélia , Johnson Bryan , Hollstein Pablo , Frederick Dennie , Cooper Zachary , Messiaen Ludwine , Bronson Roderick , McMahon Martin , Granter Scott , Flaherty Keith , Wargo Jennifer , Marais Richard , Cichowski Karen
Published: August 2014

BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations tumor development is restricted by oncogene-induced senescence (OIS). Here we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by deregulating both PI3K and ERK pathways. As such, Nf1/Braf mutant tumors are resistant to BRAF inhibitors but are sensitive to combined MEK/mTOR inhibition. Importantly, NF1 is mutated or suppressed in human melanomas that harbor concurrent BRAF mutations, NF1 ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how NF1 cooperates with BRAF mutations in melanoma and demonstrate that NF1-inactivation may impact responses to targeted therapies.

Citation Format: Ophélia Maertens, Bryan Johnson, Pablo Hollstein, Dennie Frederick, Zachary Cooper, Ludwine Messiaen, Roderick Bronson, Martin McMahon, Scott Granter, Keith Flaherty, Jennifer Wargo, Richard Marais, Karen Cichowski. Elucidating distinct roles for NF1 in melanomagenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5201. doi:10.1158/1538-7445.AM2013-5201
Abstract 5204: Downregulation of PHLLP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells.
Authors: Wen Yang-an , Gao Tianyan
Published: August 2014

Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor by negatively regulating Akt signaling in colon cancer. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia in colon cancer cells. Hypoxia-induced decrease of PHLPP expression is attenuated by silencing HIF-1α but not HIF-2α, indicating that PHLPP downregulation is HIF-1α-dependent. Whereas the mRNA levels of PHLPP are not significantly altered in hypoxia, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased protein degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated levels of mTOR activity and protein synthesis. In addition, we show that hypoxia promotes PHLPP degradation by increasing the mRNA expression of USP46, a PHLPP-specific deubiquitinase, and resulting in upregulation of PHLPP ubiquitination. Functionally, downregulation of PHLPP plays an important role in hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understand the drug resistance in cancer treatment.

Citation Format: Yang-an Wen, Tianyan Gao. Downregulation of PHLLP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2013-5204
Abstract 5222: Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach.
Authors: Kim Sangbae , Sohn Bo Hwa , Park Yun-Yong , Kim Ji-Hoon , Lee Sung Sook , Davies Micheal A. , Mills Gordon B. , Lee Ju-Seog
Published: August 2014

MicroRNAs(miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. To overcome this limitation functional target prediction approaches have been investigated with mRNA and miRNA expression data. These approaches can be used in the computational assessment of functional miRNA-target association. However, these approaches with miRNA-mRNA association were not enough to verify real functional targets at protein level, which could affect on cell signaling pathway. Therefore, in the present study to compensate this limitation, we developed a novel correlation based approach (sequence-independence) to predict potential miRNA targets with genomic and proteomic data, protein, miRNA and mRNA array data, in NCI-60 cells. To establish a prediction model for identifying the association of miRNA-cell signaling pathways by analyzing genomic and proteomic data, we performed a correlation based method among miRNA, mRNA and protein expression profile. Using this approach, we generated the Association score matrix (ASM) between miRNA and protein probes. Based on ASM, we finally generated the highly associated miRNAs with cell signaling pathways called miRNA-pathway association map (miRPM). To validate our approach, we used miR-500 as an example to investigate the hypothetical target regulation mechanisms predicted by miRPM. We confirmed in-vitro that mir-500 highly is associated with ERK/MAPK signaling pathway in melanoma and breast cancer cells. Furthermore, we found PP1/PP2 might be a direct target of miR-500 to regulate activating the ERK/MAPK pathway. In conclusion, we developed a novel expression profile based approach to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Our approach might be applied to investigate the unknown regulatory role of miRNAs in signaling pathways and gene regulatory networks.

Citation Format: Sangbae Kim, Bo Hwa Sohn, Yun-Yong Park, Ji-Hoon Kim, Sung Sook Lee, Micheal A. Davies, Gordon B. Mills, Ju-Seog Lee. Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5222. doi:10.1158/1538-7445.AM2013-5222
Abstract 5228: Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers.
Authors: Zapperi Stefano , Laporta Caterina Anna Maria
Published: August 2014

The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells.

Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.

Citation Format: Stefano Zapperi, Caterina Anna Maria Laporta. Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5228. doi:10.1158/1538-7445.AM2013-5228

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5255: The comparison between MAPK and PI3K signaling pathway inhibition in KRAS mutant NSCLC cell lines.
Authors: Dogan Irem , Cihan Ayla , Ekmekci Abdullah
Published: August 2014

Introduction: KRAS mutations are found 15-25% of patients with lung adenocarcinoma and they lead to constitutive activation of KRAS signaling pathway that results in sustained cell proliferation. Currently, there are no direct anti-KRAS therapies available. Therefore, it is rational to target the downstream molecules of KRAS signaling pathway. MAPK signaling pathway (RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR PI3K/Akt) are the activated pathways by KRAS signaling and crucial for cell survival and proliferation in non-small cell lung cancer (NSCLC). Here, we examined the inhibition of both these pathways combination and alone and analyzed the anti-proliferative and apoptotic events in KRAS mutant NCSLC cell lines, A549 and Calu-1.

Materials and Methods: Cytotoxicity was determined by MTT assay after the cells were treated with LY294002 (PI3K inhibitor), U0126 (MEK inhibitor) and RAD001 (mTOR inhibitor) for 24 hour. The expression levels of p-EGFR, EGFR, p-ERK, ERK, AKT, p-AKT, p53, cyclinD1, c-myc, p27kip1, BAX, BIM and GAPDH were detected by Western blot after 6 and 24 hour treatment.

Results: In proliferation assays, combination of RAD001 (100nM) with U0126 (10uM) and LY294002 (10uM) resulted in higher cytotoxic activity than single agents alone at 24 hour in both cell lines. Western blots revealed that U0126 directly inhibited the phosphorylation of ERK at 6 and 24 hour, followed by inhibiting the activations of its downstream molecules, including cyclinD1 and c-myc but increased the expression of p27kip1, BAX and BIM at 6 and 24 hour. On the other hand, LY294002 downregulated p-AKT signaling only at 6 hour, but not in 24 hour. However, LY294002 and RAD001 combination was effective on cyclinD1 and c-myc expression at 24 hour which can correlate with their cytotoxic effect. Although PI3K/mTOR inhibition is more effective in cytotoxicity, MEK/mTOR inhibition markedly decreases cell proliferation protein marker expressions.

Conclusion: These findings suggest that the combination of MEK and mTOR inhibitors and PI3K and mTOR inhibitors compared with either drug alone can inhibit cell proliferation, induce apoptosis and effect downstream signaling pathways. Also, in molecular level, U0126/RAD001 combination is a better option than LY294002/RAD001 combination in A549 and Calu-1 cells.

Citation Format: Irem Dogan, Ayla Cihan, Abdullah Ekmekci. The comparison between MAPK and PI3K signaling pathway inhibition in KRAS mutant NSCLC cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5255. doi:10.1158/1538-7445.AM2013-5255

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5277: MicroRNA expression profile of astrocytoma in archived formalin-fixed paraffin-embedded brain tumor samples.
Authors: Rivera-Díaz Mónica , Quintero Mario , López Julio , Vivas-Mejia P E.
Published: August 2014

Astrocytomas, a tumor derived from astrocytic glial cells, are the most common type of adult primary central nervous system (CNS) neoplasms, representing around 76% of all primary brain tumors. The World Health Organization (WHO) classified astrocytomas into four histological grades spanning from grade I, a benign tumor, to grade IV, a highly malignant tumors. This classification is somewhat subjective and more reliable molecular markers for tumor grading are necessary. MicroRNAs (miRNAs) are small (≈22-nucleotide) noncoding RNAs that, in mammals, regulate genes at the translational level by binding to loosely complimentary sequences in the 3’-UTR of target mRNAs. There is increased in vitro and in vivo evidence that various miRNAs are deregulated in a variety of cancer including astrocytoma. The aim of this study was to assess miRNAs dysregulated in astrocytoma according to its grade using archived formalin-fixed paraffin-embedded (FFPE) samples. Total RNA was isolated, labeled, and hybridized to Affymetrix miRNA arrays. Images were analyzed using the PARTEK software. Eighty-five miRNAs were differentially regulated in grade II, 72 miRNAs in grade III and 118 miRNAs in GBM; compared with control samples. Several non-previously described miRNA in astrcoytoma were identified in this study. The most differentially expressed miRNAs in each tumor grade, were selected for further validation by TAqMan-based real-time PCR. Particularly, miR-92b was upregulated in all astrocytoma grades. Opposite, miR-548p, a miRNA regulating antiapoptotic molecules, was downregulated in GBM tumor tissues, and in well-established GBM cell lines. However, the role of these miRNAs in GBM cells has not been studied. We are currently performing in vitro studies to clarify the role of some of these microRNAs in the cell proliferation of GBM cells.

Citation Format: Mónica Rivera-Díaz, Mario Quintero, Julio López, P E. Vivas-Mejia. MicroRNA expression profile of astrocytoma in archived formalin-fixed paraffin-embedded brain tumor samples. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5277. doi:10.1158/1538-7445.AM2013-5277
Abstract 5293: Prognostic significance of miR-194 in endometrial cancer.
Authors: Zhai Haiyan , Karaayvaz Mihriban , Dong Peixin , Sakuragi Noriaki , Ju Jingfang
Published: August 2014

Endometrial cancer (EC) is the leading malignant tumor occurring in the female genital tract and some subtypes are highly invasive and metastatic. miRNAs are small non-coding RNAs that have a broad impact on cancer progression. In particular, miR-194 regulates epithelial to mesenchymal transition (EMT) by suppressing the expression of BMI-1 in EC. In this retrospective study, the clinical significance of miR-194 was investigated in archival EC specimens. We extracted total RNA from thirty-two EC samples and quantified the expression level of miR-194. We discovered that the expression level of miR-194 was significantly (P = 0.03) lower in type I EC patients with more advanced stage. In addition, patients with higher miR-194 levels have better prognosis than those with lower miR-194 levels (P = 0.0067; Cut-off value of miR-194 = 0.3). These results indicate that miR-194 has potential to serve as prognostic biomarker for EC patients.

Citation Format: Haiyan Zhai, Mihriban Karaayvaz, Peixin Dong, Noriaki Sakuragi, Jingfang Ju. Prognostic significance of miR-194 in endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5293. doi:10.1158/1538-7445.AM2013-5293
Abstract 5300: Identification and validation of novel autoantibodies for the detection of malignant mesothelioma.
Authors: Zhang Xufei , Zhao Lei , Shen Weike , Kernstine Kemp , Zhong Li
Published: August 2014

Malignant mesothelioma (MM) survival rate has been hampered by the lack of efficient and accurate early detection methods. The immune system may detect the early changes of tumor progression by responding with tumor-associated autoantibody production. Hence, in this study, we translated the humoral immune response to cancer proteins into a valuable blood test for MM. A T7 phage MM cDNA library was constructed using MM tumor tissues and biopanned for tumor-associated antigens (TAAs) using pooled MM patients and normal serum samples. About 1000 individual phage TAAs clones from the biopanned library were subjected for protein microarray construction and tested with 53 MM and 52 controls serum samples as a training group. The classifiers developed from the training group were further validated with 50 patient and 50 normal serum samples as an independent blind validation. Nine candidate autoantibody markers were selected by logistic regression and Treeview statistical analysis as a detecting panel. In the training set, sensitivity of 92.5% and specificity of 90.4% were reached with an AUC was 0.898 in Receiver Operating Characteristic analysis. For validation test, 86.5% sensitivity and 86.8% specificity were achieved with an AUC of 0.825. Among these 9 candidate markers, five were found to be strongly cancer associated proteins (PDIA6, MEG3, SDCCAG3, IGHG3, IGHG1). Our results achieved much greater accuracies than any other current biomarkers for MM detection and hence could be a useful tool to assess cancer risk in high-risk populations.

Citation Format: Xufei Zhang, Lei Zhao, Weike Shen, Kemp Kernstine, Li Zhong. Identification and validation of novel autoantibodies for the detection of malignant mesothelioma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5300. doi:10.1158/1538-7445.AM2013-5300

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5338: MicroRNA-CGU promotes progression and metastasis through a negative regulation of ERM protein in human gastric cancer.
Authors: Wang Chia-Siu , Tsai Ming Ming , Kuo Liang-Mou , Lin Kwang-Huei
Published: August 2014

Background: miRNAs have an important role in tumor carcinogenesis. They may act either as oncogenes or tumor suppressor genes through their regulated-target genes. The aim of this study was to identify useful biomarkers from miRNAs that might regulate the tumorigenesis or progression of gastric cancer.

Materials and Methods:

Differential miRNA profile was analyzed with a 270 miRNAs-based qRT-PCR assay in a total of 6 pairs of tumor tissues and matched non-tumor mucosa from surgical specimens. One of the top strongest up-regulated miRNAs was selected, and it was validated by qRT-PCR in fresh frozen tissues of gastrectomized specimens from gastric cancer patients. The target gene was searched and identified. The clinicopathologic correlations of the candidate miRNA and target gene were evaluated for their clinical significance.

Results:

The miR-CGU significantly increases by more than 40.2-fold (p < 0.001) in gastric cancer tissues compared with their matched adjacent nontumorous tissues (n = 109). Overexpression of miRNA was significantly associated with tumor progression that included serosal invasion, lymph node metastasis, distant metastasis and pathological stage (all p < 0.001). Higher expression of miR-CGU was significantly associated with a worse 5-year survival outcome (log rank p < 0.001, and p = 0.005, respectively). Functional assays showed that overexpression of this miRNA enhanced gastric cancer cell migration and invasion in vitro and lung metastasis formation in vivo. In addition, a target gene, ERM protein, was identified for miR-CGU. Elevated expression of miRNA in gastric cancer cells could reduce the mRNA and protein levels of ERM protein, and vice versa. Luciferase assays confirmed that miR-CGU could directly bind to the 2-8 nucleotides of 3’ untranslated region of ERM protein. Moreover, an inverse correlation between miR-CGU and ERM protein expression was observed in gastric cancer tissues. The Interaction of miR-CGU and ERM protein expression was further studied in gastric cell lines.

Conclusion:

The miR-CGU is highly upreglated in gastric cancer tissues. It functions as a tumor metastasis enhancer in gastric cancer, and its overexpression contributes to lymph node metastasis and progression of gastric cancer. Overexpression of its target gene, ERM protein may have a therapeutic potential to suppress gastric cancer metastasis.

Citation Format: Chia-Siu Wang, Ming Ming Tsai, Liang-Mou Kuo, Kwang-Huei Lin. MicroRNA-CGU promotes progression and metastasis through a negative regulation of ERM protein in human gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5338. doi:10.1158/1538-7445.AM2013-5338
Abstract 5340: MicroRNA-720 promotes cell proliferation and invasion in prostate cancer cells.
Authors: Yamamura Soichiro , Chiyomaru Takeshi , Fukuhara Shinichiro , Saini Sharanjot , Majid Shahana , Deng Guoren , Shahryary Vary , Arora Sumit , Chang Inik , Tanaka Yuichiro , Carroll Peter , Dahiya Rajvir
Published: August 2014

MicroRNAs (miRNAs) are highly conserved, single stranded, non-coding RNAs of approximately 21 - 24 nucleotides that regulate gene expression by posttranscriptional silencing of specific target RNAs, by repressing translation or cleaving RNA transcripts by binding to the 3’ untranslated region (3’UTR) of the target messenger RNAs. miRNAs regulate diverse cellular processes such as cell-cycle progression, proliferation, apoptosis and development. miRNAs also have been shown to function as oncogenes or tumor suppressor genes.

MicroRNA profiling has shown that miR-720 was up-regulated in cancer tissues, however the function of miR-720 in cancer has not been studied. Here we studied the functional effects of miR-720 on prostate cancer cells. We found that miR-720 was up-regulated in human prostate cancer tissues compared to adjacent normal tissues. We also found that miR-720 was up-regulated in prostate PC-3 cancer cell line compared with normal prostate cell line, RWPE1 cells. Transfection of miR-720 into prostate cancer cells, PC-3 and DU145 cells, decreased apoptosis, promoted cell proliferation and cell invasion. Transfection of anti-miR-720 into PC-3 cells increased apoptosis, inhibited cell proliferation and cell invasion. These results indicated that miR-720 has oncogenic functions in prostate cancer cells. In-silico analysis suggests that miR-720 targets genes of DR1, a down-regulator of global transdcription, and SWI5, a component of a complex required for double-strand break repair, which have tumor suppressive functions. Luciferase assays indicated that miR-720 binds to the 3’ UTR of these genes in prostate cancer cells, suggesting that these genes are targets of miR-720. Our results suggest that miR-720 promotes malignancy by targeting DR1 and SWI5 in prostate cancer cells.

Funding: National Institutes of Health through Grant Number RO1CA138642, RO1CA130860 and RO1CA160079 and VA Merit Review and VA Program Project.

Citation Format: Soichiro Yamamura, Takeshi Chiyomaru, Shinichiro Fukuhara, Sharanjot Saini, Shahana Majid, Guoren Deng, Vary Shahryary, Sumit Arora, Inik Chang, Yuichiro Tanaka, Peter Carroll, Rajvir Dahiya. MicroRNA-720 promotes cell proliferation and invasion in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5340. doi:10.1158/1538-7445.AM2013-5340
Abstract 5378: Inhibition of 15-hydroxyprostaglandin dehydrogenase by Helicobacter pylori in human gastric carcinogenesis.
Authors: Ryu Yeon Mi , Myung Seung-Jae , Park3 Young Soo , Song Ho June , Yang Dong-Hoon , Jeong Jin-Yong , Lee Sun Mi , Song Miyeoun , Kim Do Hoon , Lee Hyo-Jeong , Fink Stephen P. , Markowitz Sandy D. , Jung Kee Wook , Kim Kyung-Jo , Ye Byong Duk , Byeon Jung-Sik , Jung Hwoon-Yong , Yang Suk-Kyun , Kim Jin-Ho
Published: August 2014

Helicobacter pylori (H pylori) infection induces a chronic inflammatory response, which promotes gastric carcinogenesis. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) plays a key role as a tumor suppressor in gastrointestinal cancers. The aim of this study was to elucidate the role of 15-PGDH in gastric carcinogenesis associated with H pylori. 15-PGDH expression in gastric biopsies from H pylori-infected (n=25) and non-infected (n=15) subjects was analyzed by quantitative real-time PCR, western blot analysis, and immunohistochemisty. 15-PGDH DNA methylation was evaluated by methylation specific PCR and pyrosequencing. The expression of 15-PGDH, Snail, ERK1/2, TLR4 and MyD88 in response to H pylori infection was assessed by immunoblot analysis. Compared to negative specimens, H pylori positive specimens had 2-fold lower 15-PGDH mRNA levels and significantly less 15-PGDH protein. In four H pylori infected subjects with longitudinal follow-up, the suppression of 15-PGDH expression was reversed by H pylori eradication therapy. In parallel with suppressing 15-PGDH expression, H pylori infection activated expression of TLR4 and MyD88 expression, increased levels of phospho-ERK1/2, and increased expression of Snail. Inhibition of MyD88 reversed suppression of 15-PGDH expression and reduced phosphorylated ERK1/2. Similarly, treatment with an ERK1/2 inhibitor also restored 15-PGDH expression. Heliocobacter pylori appeared to promote gastric carcinogenesis by suppressing15-PGDH. This process is mediated by the TLR4/MyD88 pathway via ERK1/2 and Snail transcriptional regulation. 15-PGDH may be a useful marker and a potential therapeutic target in H pylori-induced gastric carcinogenesis.

Citation Format: Yeon Mi Ryu, Seung-Jae Myung, Young Soo Park3, Ho June Song, Dong-Hoon Yang, Jin-Yong Jeong, Sun Mi Lee, Miyeoun Song, Do Hoon Kim, Hyo-Jeong Lee, Stephen P. Fink, Sandy D. Markowitz, Kee Wook Jung, Kyung-Jo Kim, Byong Duk Ye, Jung-Sik Byeon, Hwoon-Yong Jung, Suk-Kyun Yang, Jin-Ho Kim. Inhibition of 15-hydroxyprostaglandin dehydrogenase by Helicobacter pylori in human gastric carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5378. doi:10.1158/1538-7445.AM2013-5378
Abstract 5381: p62/IMP2 promotes hepatocellular carcinoma (HCC) progression.
Authors: Lei Ningjing , Peng Bo , Li Yang , Chai Yurong , Zhang Jianying
Published: August 2014

Autoantibodies to autologous cellular antigens in cancer patients have been considered as reporters identifying antigenic changes in cellular factors involved in the transformation process. We have made use of such autoantibodies from hepatocellular carcinoma patients to immunoscreen a cDNA expression library and have identified a cytoplasmic RNA-binding protein p62. Autoantibodies to p62 have been detected in up to 21% of a cohort of hepatocellular carcinoma (HCC) patients. Further study has demonstrated that p62 is a member of insulin-like growth factor 2 mRNA binding protein family (IMPs), which is an isoform of IMP2. The three members of the IMP family (IMP1, 2 and 3) have been found to regulate translation of insulin-like growth factor 2 (IGF2) mRNA in a post-transcriptional manner. Since several studies have suggested that IMP1 and IMP3 play important roles in cancer progression, whether p62/IMP2 can also play a role in cancer formation remains to be investigated. In this study, we intend to interrogate the role of p62/IMP2 in HCC formation. We found that the expression of p62/IMP2 (57.5%) is significantly higher in HCC specimen than that in normal liver tissue (15.4%) by immunohistochemistry study. Furthermore, p62/IMP2 is detected to be overexpressed in several liver cancer cell lines. Depletion of p62/IMP2 via lentivirus-mediated knockdown in SNU449 liver cancer cell line decreased the cell proliferation. On the contrary, the ectopic overexpression of p62/IMP2 increased cell proliferation. Our data suggested that p62/IMP2 is overexpressed in liver cancer and is functionally correlated with cancer cell growth.

Citation Format: Ningjing Lei, Bo Peng, Yang Li, Yurong Chai, Jianying Zhang. p62/IMP2 promotes hepatocellular carcinoma (HCC) progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5381. doi:10.1158/1538-7445.AM2013-5381
Abstract 5397: MYC-driven glutamine metabolism promotes antiestrogen resistance in breast cancer.
Authors: Shajahan Ayesha N. , Cook Katherine L. , Schwartz-Roberts Jessica L. , Eltayeb Ahreej E. , Demas Diane M. , Warri Anni , Hilakivi-Clarke Leena , Metallo Steven , Clarke Robert
Published: August 2014

About 70% of newly diagnosed cases of invasive breast cancer in the U.S. will be estrogen receptor alpha positive (ER+). Endocrine therapy is the least toxic and most effective means to manage the hormone-dependent breast cancer, administered as an antiestrogen, e.g., Tamoxifen (TAM) or Faslodex (FAS; Fulvestrant; ICI 182,780) or an aromatase inhibitor (AI), e.g., Letrozole (LET). However, advanced ER+ breast cancer that has become resistant to endocrine therapy remains a significant clinical problem. Here we show that in breast cancer cells and rat tumors with acquired antiestrogen resistance, MYC, a oncogenic transcription factor, is overexpressed. Inhibition of MYC with small molecule inhibitor or siRNA resensitizes resistant cells to antiestorgens by inducing apoptosis. MYC inhibition in resistant cells also inhibited glutamine uptake and decreased levels of ASCT2/SLC1A5, a glutamine transporter. Resistant cells showed significant increase in cell proliferation in response to glutamine than sensitive cells. Moreover, resistant cells showed increased sensitivity to an inhibitor of glutaminase, GLS, an enzyme that hydrolysis of glutamine to glutamate. Thus, MYC promotes increased dependence on glutamine in antiestrogen resistant cells, and targeting glutamine metabolism could help circumvent antiestrogen resistance. Overreaching goal of this study is to and to identify effective therapies to treat endocrine resistant breast cancer.

Citation Format: Ayesha N. Shajahan, Katherine L. Cook, Jessica L. Schwartz-Roberts, Ahreej E. Eltayeb, Diane M. Demas, Anni Warri, Leena Hilakivi-Clarke, Steven Metallo, Robert Clarke. MYC-driven glutamine metabolism promotes antiestrogen resistance in breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5397. doi:10.1158/1538-7445.AM2013-5397
Abstract 5398: TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520.
Authors: Park Yun-Yong , Kim Sang Bae , Han Hee Dong , Sohn Bo-Hwa , Liang Jiyong , Lu Yiling , Mills Gordon , Sood Anil , Lee Ju-Seog
Published: August 2014

Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the miR-520 family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which in turn inhibited expression of PFKP. We further showed that expression of PFKP is significantly associated with the overall survival of patients with HCC. Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC.

Citation Format: Yun-Yong Park, Sang Bae Kim, Hee Dong Han, Bo-Hwa Sohn, Jiyong Liang, Yiling Lu, Gordon Mills, Anil Sood, Ju-Seog Lee. TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2013-5398
Abstract 5404: Metabolic stress played a role in dasatinib-induced EGFR degradation and apoptosis in head and neck cancer.
Authors: Lin Yu-Chin , Wu Meng-Hsuan , Wei Tzu-Tang , Chen Kuen-Feng , Cheng Ann-Lii , Chen Ching-Chow
Published: August 2014

Head and neck squamous cell carcinoma (HNSCC) is a worldwide disease with aggressive course and dismal outcome. Dasatinib, a Bcr-abl and Src in hibitor, has been approved clinically for CML and shown activities against solid tumors in vitro. In our recent work, degradation of epidermal growth factor receptor (EGFR) plays a role in dasatinib-induced apoptosis in HNSCC cells. We further revealed the role of metabolic stress in dasatinib-induced EGFR degradation and apoptosis. Dasatinib decreased cellular ATP, and activated AMPK activation and induced endoplasmic reticulum stress (ER stress) as well. Inhibition or knockdown of AMPK reversed dasatinib-induced EGFR degradation, and pharmacological activation of AMPK led to ER stress and EGFR degradation. Addition of ER stress inhibitor to dasatinib reversed EGFR degradation and apoptosis, and pharmacologic activation of ER stress resulted in EGFR degradation. In conclusion, metabolic stress may play a role in dasatinib-induced EGFR degradation and apoptosis in HNSCC cells.

Citation Format: Yu-Chin Lin, Meng-Hsuan Wu, Tzu-Tang Wei, Kuen-Feng Chen, Ann-Lii Cheng, Ching-Chow Chen. Metabolic stress played a role in dasatinib-induced EGFR degradation and apoptosis in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5404. doi:10.1158/1538-7445.AM2013-5404
Abstract 5408: Enhancement of the anti-tumor activity of afatinib by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation .
Authors: Cho Byoung Chul , Kim Hyun-Jung , Lim Sun Min
Published: August 2014

The secondary epidermal growth factor receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-D-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR, which are NSCLC cells with EGFR T790M. Treatment with a combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9-GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through inhibition of mammalian target of rapamycin (mTOR). The alteration of the AMPK/mTOR signaling pathway by inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of anti-apoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by treatment of 2DG was confirmed in in vivo PC9-GR xenograft model. In conclusion, this study examined whether inhibition of glucose metabolism using 2DG enhances the sensitivity to afatinib in NSCLC cells with EGFR T790M through regulation of AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for treatment of patients with acquired resistance to reversible EGFR TKIs due to secondary EGFR T790M.

Citation Format: Byoung Chul Cho, Hyun-Jung Kim, Sun Min Lim. Enhancement of the anti-tumor activity of afatinib by inhibition of glycolysis in non-small cell lung cancer harboring the EGFR T790M mutation . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5408. doi:10.1158/1538-7445.AM2013-5408

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5410: Modulating metabolic homeostasis as a therapeutic tool for leukemia.
Authors: Attia Ramy R. , Min Jaeki , Guy Rodney K.
Published: August 2014

Genetic studies in humans and rodents support the notion that alterations in metabolic homeostasis can directly contribute to carcinogenesis and metabolic processes may be targets for therapy. The nuclear hormone receptors (NR) control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters, and other mediators. Therefore we explored potential links between cellular metabolic control by NRs and viability of cancer cells. In this study we tested the effect of 127 NR modulators, targeting receptors known to be important in regulating metabolism or known to be viable cancer targets on the growth of different leukemic cells lines. Of the compounds tested 8, mainly targeting ER and RAR, induced significant apoptosis in these leukemias. The effects of the 8 active compounds on mitochondrial metabolism were tested in Jurkat cells and 5 compounds significantly reduced lactate levels. However, only the synthetic retinoid (CD437) significantly affected pyruvate dehydrogenase complex activity. CD437 also effected the expression of genes involved in leukemia development and therapeutic responses with the PKC pathway being the primary target. CD437 induced PKC Kinase activity and activated its downstream signals AKT and JNK. CD437 downregulated CPT-1a,and decreased the overall O2 consumption rate. Additional CD437 induced genes included those involved in the mitochondrial respiratory complex I and III and increased the production of ROS. Our results indicate that the apoptotic effect of CD437 can be linked to its regulation of mitochondrial oxidative metabolism.

Citation Format: Ramy R. Attia, Jaeki Min, Rodney K. Guy. Modulating metabolic homeostasis as a therapeutic tool for leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5410. doi:10.1158/1538-7445.AM2013-5410
Abstract 5415: Targeting lipogenic signaling to repress cancer cell growth.
Authors: Wang Chenguang , Li Weihua , Zhou Jie , Tai Yanhong , Gu Weiting , Das Bhaskar C. , Ji Junyuan
Published: August 2014

The significantly enhanced lipogenesis is a metabolic hallmark of rapidly proliferating tumor cells. Although most normal cells acquire the bulk of their fatty acids from circulation, tumor cells synthesize more than 90% of required lipids de novo. The sterol regulatory element-binding protein 1 (SREBP1), encoded by SREBF1 gene, is a master regulator of lipogenic gene expression. Although it is known that SREBP1 and its target genes are overexpressed in a variety of cancers, the role of SREBP1 in endometrial cancer is largely unknown. Herein, we screened a panel of endometrial cancer specimen for their lipogenic gene expression by quantitative PCR and showed a significant increase in mRNA abundance of SREBF1, SREBF2, and FASN genes in cancer compared to normal endometrium. Immunohistochemical staining confirmed SREBP1 protein overexpression and further demonstrated increased nuclear distribution of SREBP1 in EC. SREBP1 promotes cellular proliferation in cell culture and enhances tumor growth in a xenograft model. Knockdown of endogenous SREPF1 gene impaired the viability of cells cultured in medium supplemented with lipid-depleted serum. BF175, a small molecule inhibitor designed to target SREBP1, repressed SREBP1-dependent gene expression and cell growth and induced EC cell death. We extended our observation to over 100 cancer cell lines from 12 different cancer types and showed promising results of BF175 in repressing tumor growth and inducing cell death. Together, this study established a role of SREBP1 in tumor growth and validated BF175 for its therapeutic effectiveness in targeting SREBP1 and lipogenesis to block cancer cell growth.

Citation Format: Chenguang Wang, Weihua Li, Jie Zhou, Yanhong Tai, Weiting Gu, Bhaskar C. Das, Junyuan Ji. Targeting lipogenic signaling to repress cancer cell growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5415. doi:10.1158/1538-7445.AM2013-5415