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Oncology 1. The MDM2-p53 pathway revisited. J Biomed Res, 2013,27(4):254-271 Subhasree Naga, Jiangjiang Qina, Kalkunte S. Srivenugopalb,c, Minghai Wangb,c, Ruiwen Zhanga,b a Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; b Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA; c Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. Abstract: The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR130402&flag=1 2. Clinicopathologic significance of CXCR4 and Nrf2 in colorectal cancer. J Biomed Res, 2013,27(4):283-290 Tinghua Hua, Yu Yaoa, Shuo Yub, Hui Guoa, Lili Hana, Wenjuan Wanga, Tao Tiana, Yibin Haoc, Zhiyan Liud, Kejun Nana, Shuhong Wanga Departments of aOncology and bHepatobiliary Surgery, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; c Department of Pediatrics, Zhengzhou Central Hospital, Zhengzhou, Henan 450007, China; d Department of respiration, Xi'an Central Hospital, Xi'an, Shaanxi 710003, China. Abstract: The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer (CRC) tissue specimens and investigated their correlation with patient clinicopathologic characteristics. We determined CXCR4 and Nrf2 expression in 76 CRC tissue specimens and paired normal tissue specimens by immunohistochemistry and real-time PCR. We found that the protein and mRNA transcript levels of CXCR4 were significantly higher in CRC tissue specimens than in paired normal tissues, while the expressions of Nrf2 protein and mRNA were increased in CRC tissues compared to distant non-cancerous tissues. High expression level of CXCR4 was positively correlated with poorly differentiated (P = 0.031), more advanced tumor-node-metastasis (TNM) stage (P = 0.019), lymph node metastasis (P = 0.007) and distant metastasis (P = 0.018). However, the expression of Nrf2 protein was positively correlated with larger tumor size (P = 0.049), more advanced TNM stage (P = 0.013), lymph node metastasis (P = 0.016) and distant metastasis (P = 0.023). Moreover, there was a strong relationship between CXCR4 and Nrf2 expression in CRC tissues, indicating that high Nrf2 expression may contribute to CXCR4 overexpression. In addition, combined expression of CXCR4 and Nrf2 strongly correlated with lymph node metastasis and distant metastasis (P = 0.003). Furthermore, we found that combined high expression of CXCR4 and Nrf2 had stronger correlation with lymph node metastasis and distant metastasis than any single molecule did. This study indicated that the abnormal expression of CXCR4 and Nrf2 contributed to the progression of CRC. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR130404&flag=1 3. Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction. J Biomed Res,2013,27(5):345-356 Ming-Hai Wanga,b, , Ruiwen Zhanga,c, Yong-Qing Zhoud, Hang-Ping Yaoe a Cancer Biology Research Center, bDepartment of Biomedical Sciences, and cDepartment of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79119, USA; d Department of Neurosurgery and eViral Oncogenesis Section in State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China. Abstract: The RON receptor tyrosine kinase, a member of the MET proto-oncogene family, is a pathogenic factor im-plicated in tumor malignancy. Specifically, aberrations in RON signaling result in increased cancer cell growth, survival, invasion, angiogenesis, and drug resistance. Biochemical events such as ligand binding, receptor over-expression, generation of structure-defected variants, and point mutations in the kinase domain contribute to RON signaling activation. Recently, functional crosstalk between RON and signaling proteins such as MET and EFGR has emerged as an additional mechanism for RON activation, which is critical for tumorigenic develop-ment. The RON signaling crosstalk acts either as a regulatory feedback loop that strengthens or enhances tumor-igenic phenotype of cancer cells or serves as a signaling compensatory pathway providing a growth/survival ad-vantage for cancer cells to escape targeted therapy. Moreover, viral oncoproteins derived from Friend leukemia or Epstein-Barr viruses interact with RON to drive viral oncogenesis. In cancer cells, RON signaling is integrated into cellular signaling network essential for cancer cell growth and survival. These activities provide the mo-lecular basis of targeting RON for cancer treatment. In this review, we will discuss recent data that uncover the mechanisms of RON activation in cancer cells, review evidence of RON signaling crosstalk relevant to cancer malignancy, and emphasize the significance of the RON signaling addiction by cancer cells for tumor therapy. Understanding aberrant RON signaling will not only provide insight into the mechanisms of tumor pathogenesis, but also lead to the development of novel strategies for molecularly targeted cancer treatment. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR130501&flag=1 4. Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients. J Biomed Res, 2013,27(6):478-485 Xiaojian Nia, Yingchun Zhaob, Jingjing Mac, Tiansong Xiaa, Xiaoan Liua, Qiang Dinga, Xiaoming Zhaa, Shui Wanga a Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; b Department of Breast Surgery, The Second People's Hospital Affiliated with Wannan Medical College, Wuhu, Anhui 241000, China; c State Key Laboratory of Reproductive Medicine, Department of Breast Surgery, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Hypoxia-induced factor-1 alpha (HIF-1α) affects many effector molecules and regulates tumor lymphangio-genesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regu-lation of vascular endothelial growth factor C (VEGF-C) expression and its effect on lymphangiogenesis and an-giogenesis in breast cancer. Lymphatic vessel density (LVD), microvessel density (MVD) and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C (P = 0.014, r = 0.273, Spearman's coefficient of correlation). HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD (P = 0.003 and P = 0.017, re-spectively), regional lymph nodal involvement (P = 0.002 and P = 0.004, respectively) and advanced tumor, node, metastasis (TNM) classification (P = 0.001 and P = 0.01, respectively). Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C (P = 0.033 and P = 0.037, respectively). Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF-1α as a therapeutic target against tumor lymph node me-tastasis. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR130606&flag=1 5. The miR-183~96~182 cluster promotes tumorigenesis in a mouse model of medulloblastoma. J Biomed Res, 2013,27(6):486-494 Zengdi Zhang, Sanen Li, Steven Y Cheng Department of Developmental Genetics, Nanjing Medical University, Nanjing, Jiangsu 210029, China. Abstract: Medulloblastoma is the most common malignant pediatric brain tumor. Some are thought to originate from cerebellar granule neuron progenitors (CGNPs) that fail to undergo normal cell cycle exit and differentiation. The contribution of microRNAs to the initiation and progression of medulloblastoma remains poorly understood. Increased expression of the miR-183~96~182 cluster of microRNAs has been noted in several aggressive sub-groups. We identified that expression of miR-183~96~182 was higher in medulloblastomas with Pten gene loss in the background of the activated sonic hedgehog (Shh) signaling pathway. Ectopic miR-183~96~182 expression in CGNPs synergized with exogenous Shh to increase proliferation and its role depended on hedgehog signaling ac-tivation. Our findings suggest a new microRNA cluster, the miR-183~96~182, functionally collaborates with the Shh signaling pathway in the development of medulloblastomas in mice. http://www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR130607&flag=1