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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