MDM2 and Ki-67 Predict for Distant Metastasis and Mortality in Men Treated With Radiotherapy and Androgen Deprivation for Prostate Cancer: RTOG 92-02

Khor, Li Yan; Bae, Kyounghwa; Paulus, Rebecca; Al‐Saleem, Tahseen; Hammond, M. Elizabeth H.; Grignon, David J.; Che, Mingxin; Venkatesan, Varagur; Byhardt, Roger W.; Rotman, Marvin; Hanks, Gerald E.; Sandler, Howard M.; Pollack, Alan

doi:10.1200/jco.2008.19.8267

Cited by 88 publications

(74 citation statements)

References 26 publications

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“…Genetic profiling, pointing toward chromosomal aberrations in patients with early-stage colorectal cancer, identified patients who developed metastatic relapse (2). Murine double minute oncogene (Mdmp2) and Ki-67 are well established as important predictors of metastasis in some cancers (3). However, identifying a prognostic marker that would be common to various cancers in their ability to predict development of metastasis or recurrence is of utmost importance.…”

Section: Introductionmentioning

confidence: 99%

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

Lee

Murthy²,

Cawley³

et al. 2011

J. Clin. Invest.

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Metastasis is a major cause of mortality in cancer patients. However, the mechanisms governing the metastatic process remain elusive, and few accurate biomarkers exist for predicting whether metastasis will occur, something that would be invaluable for guiding therapy. We report here that the carboxypeptidase E gene (CPE) is alternatively spliced in human tumors to yield an N-terminal truncated protein (CPE-ΔN) that drives metastasis. mRNA encoding CPE-ΔN was found to be elevated in human metastatic colon, breast, and hepatocellular carcinoma (HCC) cell lines. In HCC cells, cytosolic CPE-ΔN was translocated to the nucleus and interacted with histone deacetylase 1/2 to upregulate expression of the gene encoding neural precursor cell expressed, developmentally downregulated gene 9 (Nedd9) -which has been shown to promote melanoma metastasis. Nedd9 upregulation resulted in enhanced in vitro proliferation and invasion. Quantification of mRNA encoding CPE-ΔN in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity, independent of cancer stage. Similarly, high CPE-ΔN mRNA copy numbers in resected pheochromocytomas/ paragangliomas (PHEOs/PGLs), rare neuroendocrine tumors, accurately predicted future metastasis or recurrence. Thus, CPE-ΔN induces tumor metastasis and should be investigated as a potentially powerful biomarker for predicting future metastasis and recurrence in HCC and PHEO/PGL patients. IntroductionCancer mortality often results from metastatic disease and is not the direct effect of the primary tumor. With advances in cancer treatment, control of the primary tumor can be managed by multimodal therapy; however, metastatic disease is frequently refractory to the same therapeutic approaches. Thus, identification of biomarkers that could accurately predict future metastasis from the state of the primary tumor would be invaluable for guiding therapy.Currently, determination of the likelihood of developing metastatic disease is based on morphological and histological criteria such as the size of the primary tumor, local invasion, tumor differentiation together with vascular and capsular invasion, and the presence of cancer cells in lymph nodes. Although these criteria put many patients in a very high-risk category for metastatic disease, a significant number of them do not develop metastatic spread. On the other hand, patients with favorable conventional prognostic factors may still develop metastasis.Numerous mechanisms have been described that modulate metastatic potential, including those both endogenous and exogenous to the tumor cells. Such alterations may recruit genes

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Section: Introductionmentioning

confidence: 99%

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

Lee

Murthy²,

Cawley³

et al. 2011

J. Clin. Invest.

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“…Discordant results were observed for MDM2 with the outcome of ACM and PSM (ACM, P ¼ 0.003; PSM, P ¼ 0.08; ref. 19). …”

Section: All-cause Mortalitymentioning

confidence: 99%

Tissue Biomarkers for Prognosis of Prostate Cancer: A Systematic Review and Meta-analysis

Zhao

Guo

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Although numerous investigators have made efforts to assess prognostic biomarkers of prostate cancer, no biomarker has been recommended for clinical practice.Methods: According to REMARK (Reporting recommendations for tumor marker prognostic studies) and MISFISHIE (Minimum information specification for in situ hybridization and immunohistochemistry experiments) guidelines, the published articles of immunohistochemistry-based prognostic biomarkers on prostate cancer were extracted and pooled.Results: Ninety-three prognostic biomarkers from 92 high-quality cohort studies were included in this metaanalysis. Our analysis reveals some promising independent prognostic biomarkers, including Ki-67 [all-cause mortality (ACM) HR, 1.85; 95% confidence interval

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“…One study of 100 tumor samples taken from patients with esophageal squamous cell carcinoma revealed that MDM2 expression is the most significant risk factor for distant metastases (26). A recent series of studies indicate that MDM2 overexpression is associated with cancer metastases and predicts a poor prognosis for developing metastatic, but not localized, cancer (14,19,32,41). It has been reported that MDM2 expression is correlated with increased levels of the angiogenic factor vascular endothelial growth factor (VEGF) (31,42), which may facilitate vascularization, as well as intravasation and seeding of tumor cells in distant places, thus actively contributing to tumor metastasis.…”

mentioning

confidence: 99%

MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia

Zhou

et al. 2011

Molecular and Cellular Biology

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Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significantly higher upregulation of both VEGF mRNA and protein in MDM2-positive cells than in the MDM2-negative cells, even in cells without wild-type (wt) p53. We found that hypoxia induced translocation of MDM2 from the nucleus to the cytoplasm, which was associated with increased VEGF expression. Enforcing overexpression of cytoplasmic MDM2 by transfection of the mutant MDM2/166A enhanced expression of VEGF mRNA and protein production, even without hypoxia. The results of mechanistic studies demonstrated that the C-terminal RING domain of the MDM2 protein bound to the AU-rich sequence within the 3 untranslated region (3UTR) of VEGF mRNA; this binding increased VEGF mRNA stability and translation. In addition, knockdown of MDM2 by small interfering RNA (siRNA) in MDM2-overexpressing cancer cells resulted in inhibition of VEGF protein production, cancer cell survival, and angiogenesis. Our results suggest that MDM2 plays a p53-independent role in the regulation of VEGF, which may promote tumor growth and metastasis.The MDM2 protein is a multifunctional oncoprotein that has been shown to play both p53-dependent and -independent roles in oncogenesis. Normally, MDM2 is a nuclear phosphoprotein that contains several conserved functional regions. The MDM2 NH 2 terminus is well characterized; it binds to p53 and represses p53-mediated transcription (30). Thus, it suppresses tumor suppressor activity. The COOH terminus contains a RING finger domain that is an E3 ligase that can regulate ubiquitination of p53 and MDM2 itself (16). Early studies show that in addition to its activity as an E3 ligase, the COOHterminal RING finger domain of MDM2 is able to directly bind specific RNA sequences or structures, at least in vitro (11,22). Recently published studies, including ours, show that the MDM2 RING finger domain binds to many cellular mRNAs, such as p53 and X-linked inhibitor of apoptosis (XIAP) mRNAs, in vivo, regulating mRNA translation and protein synthesis (5, 15).MDM2 gene amplification occurs in diverse human malignancies that include soft tissue sarcomas, neuroblastoma, and cancers of the brain, breast, ovary, cervix, lung, colon, prostate, and bone (9,23,29). In addition, high-level MDM2 expression can occur even in cancers without MDM2 gene amplification, sometimes associated with a single nucleotide polymorphism in the MDM2 gene promoter (3). Thus, overexpression of MDM2 appears to be a favorable state for cancer cells. In fact, in the clinic, overexpression of MDM2 in tumors does correlate with a poor prognosis for cancer patients (34). In addition, previous studies show that MDM2 overexpression occurs more frequently in metastatic and recurrent cancers than in primary tumors (10, 21). One study of 100 tumo...

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MDM2 and Ki-67 Predict for Distant Metastasis and Mortality in Men Treated With Radiotherapy and Androgen Deprivation for Prostate Cancer: RTOG 92-02

Cited by 88 publications

References 26 publications

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

Tissue Biomarkers for Prognosis of Prostate Cancer: A Systematic Review and Meta-analysis

MDM2 Regulates Vascular Endothelial Growth Factor mRNA Stabilization in Hypoxia

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