Gholamreza Safaee Ardekani

The Prognostic Value of BRAF Mutation in Colorectal Cancer and Melanoma: A Systematic Review and Meta-Analysis

Background Mutation of BRAF is a predominant event in cancers with poor prognosis such as melanoma and colorectal cancer. BRAF mutation leads to a constitutive activation of mitogen activated protein kinase pathway which is essential for cell proliferation and tumor progression. Despite tremendous efforts made to target BRAF for cancer treatment, the correlation between BRAF mutation and patient survival is still a matter of controversy. Methods/Principal Findings Clinical studies on the correlation between BRAF mutation and patient survival were retrieved from MEDLINE and EMBASE databases between June 2002 and December 2011. One hundred twenty relevant full text studies were categorized based on study design and cancer type. Publication bias was evaluated for each category and pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using random or fixed effect meta-analysis based on the percentage of heterogeneity. Twenty six studies on colorectal cancer (11,773 patients) and four studies on melanoma (674 patients) were included in our final meta-analysis. The average prevalence of BRAF mutation was 9.6% in colorectal cancer, and 47.8% in melanoma reports. We found that BRAF mutation increases the risk of mortality in colorectal cancer patients for more than two times; HR = 2.25 (95% CI, 1.82–2.83). In addition, we revealed that BRAF mutation also increases the risk of mortality in melanoma patients by 1.7 times (95% CI, 1.37–2.12). Conclusions We revealed that BRAF mutation is an absolute risk factor for patient survival in colorectal cancer and melanoma.

Sox4-mediated Dicer expression is critical for suppression of melanoma cell invasion

We previously reported reduced expression of Sox4 in metastatic melanoma and its role in suppression of cell migration and invasion through inhibition of nuclear factor (NF)-κB p50. Sox4 can also bind to the promoter sequence of Dicer, a microRNA (miRNA) biogenesis factor. Interestingly, altered expression of Dicer was also observed in cancers. However, the potential mechanisms that regulate Dicer expression and its potential significance in melanoma progression are unknown. Here, we studied the regulation of Dicer expression by Sox4 and its role in suppression of melanoma invasion. Our data showed that Sox4 positively regulates Dicer expression by binding to its promoter sequences and enhancing its activity. We found that knockdown of Dicer enhances the matrigel invasion of melanoma cells by at least twofold. In addition, we revealed that overexpression of exogenous Dicer reverts the enhanced melanoma cell invasion upon Sox4 knockdown. Furthermore, we examined the expression of Dicer protein in a large set of melanocytic lesions (n=514) at different stages by tissue microarray and found that Dicer expression is inversely correlated with melanoma progression (P<0.0001). Consistently, reduced Dicer expression was correlated with a poorer overall and disease-specific 5-year survival of patients (P=0.015 and 0.0029, respectively). In addition, we found a significant correlation between expression of Sox4 and Dicer proteins in melanoma biopsies (P=0.009), further indicating the regulation of Dicer expression by Sox4. Finally, we revealed that knockdown of Sox4 induces a major change in the expression pattern of miRNAs in melanoma cells, mainly due to reduced expression of Dicer. Our results pinpoint the regulation of Dicer expression by Sox4 in melanoma and the critical role of Dicer in suppression of melanoma invasion. Our findings on Sox4-regulated miRNA biogenesis pathway may aid toward the development of novel targeted therapeutic approaches for melanoma.

Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis

In addition to their critical roles in embryonic development, cell fate decision, and differentiation, members of Sox (Sry-related high-mobility group box) family of transcription factors including Sox4 have been implicated in various cancers. Multiple studies have revealed an increased expression along with specific oncogenic function of Sox4 in tumors, while others observed a reduced expression of Sox4 in different types of malignancies and suppression of tumor initiation or progression by this protein. More interestingly, the prognostic value of Sox4 is debated due to obvious differences between various reports as well as inconsistencies within specific studies. This review summarizes our current understanding of Sox4 expression pattern and its transcription-dependent, as well as transcription-independent, functions in tumor initiation or progression and its correlation with patient survival. We also discuss the existing discrepancies between different reports and their possible explanations.

Role of EIF5A2, a downstream target of Akt, in promoting melanoma cell invasion

Background:Cutaneous melanoma is a life-threatening skin cancer because of its poorly understood invasive nature and high metastatic potential. This study examines the importance of eukaryotic translation initiation factor 5A2 (EIF5A2) in melanoma pathogenesis.Methods:We examined EIF5A2 expression in 459 melanocytic lesions using tissue microarray. In addition, melanoma cell lines were subjected to invasion and cell proliferation assays, zymography, FACS and real-time PCR to investigate the role of EIF5A2 in cancer progression.Results:Positive EIF5A2 staining increased from dysplastic naevi to primary melanomas (PMs; P=0.001), and further increased in metastatic melanomas (P=0.044). Eukaryotic translation initiation factor 5A2 expression was correlated with melanoma thickness (P<0.001) and was inversely correlated with the 5-year survival of PM patients especially those with tumour⩽2 mm thick. Strikingly, none of the latter died within 5 years in EIF5A2-negative staining group. Cox regression analysis revealed that EIF5A2 is an independent prognostic marker. Further, we found that EIF5A2 is a novel downstream target of phosphorylated Akt. Both melanoma cell invasion and MMP-2 activity increased and decreased with EIF5A2 overexpression and knockdown, respectively.Conclusion:We for the first time showed that EIF5A2, as a target of PI3K/Akt, promotes melanoma cell invasion and may serve as a promising prognostic marker and a potential therapeutic target for melanoma.

A combination of p300 and Braf expression in the diagnosis and prognosis of melanoma

BackgroundTo date only a handful of drugs are available for the treatment of melanoma. Among them vemurafenib, a BrafV600E specific inhibitor, showed promising results in terms of response rate and increase in median survival time. However, its effectiveness is limited by development of resistance and the search for additional drugs for melanoma treatment is ongoing. The present study was performed to analyze the correlation between Braf expression and the expression of p300, a known down stream target of the mitogen activated protein kinase (MAPK) pathway, which was recently shown by us to be a prognostic marker for melanoma progression and patient survival.MethodsThe expression of Braf and p300 expression were correlated and analyzed by Chi-square test. A total of 327 melanoma patient cases (193 primary melanoma and 134 metastatic melanoma) were used for the study. Classification & regression tree (CRT), Kaplan-Meier, and multivariate Cox regression analysis were used to elucidate the significance of the combination of Braf and p300 expression in the diagnosis and prognosis of melanoma.ResultsOur results demonstrate that Braf expression is inversely correlated with nuclear p300 and positively correlated with cytoplasmic p300 expression. Braf and cytoplasmic p300 were found to be associated with melanoma progression, tumor size and ulceration status. CRT analysis revealed that a combination of Braf and p300 expression (nuclear and cytoplasmic), could be used to distinguish between nevi and melanoma, and primary from metastatic melanoma lesions. The combination of Braf and nuclear p300 was significantly associated with patient survival and nuclear p300 was found to be an independent predictor of patient survival.ConclusionOur results indicate a cross-talk between Braf and p300 in melanoma and demonstrate the importance Braf and p300 expression in the diagnosis and prognosis of melanoma.

eIF4E Is an Adverse Prognostic Marker of Melanoma Patient Survival by Increasing Melanoma Cell Invasion

Human cutaneous melanoma is a devastating skin cancer because of its invasive nature and high metastatic potential. We used tissue microarray to study the role of human eukaryotic translation initiation factor 4E (eIF4E) in melanoma progression in 448 melanocytic lesions and found that high eIF4E expression was significantly increased in primary melanomas compared with dysplastic nevi (P<0.001), and further increased in metastatic melanomas (P<0.001). High eIF4E expression was associated with melanoma thickness (P=0.046), and poor overall and disease-specific 5-year survival of all, and primary melanoma patients, especially those with tumors ≥1 mm thick. Multivariate Cox regression analysis revealed that eIF4E is an independent prognostic marker. eIF4E knockdown (KD) in melanoma cells resulted in a significant increase in apoptosis (sub-G1 populations) and decrease in cell proliferation, and also resulted in downregulation of mesenchymal markers and upregulation of E-cadherin. In addition, eIF4E KD led to a decrease in melanoma cell invasion, matrix metalloproteinase-2 expression and activity, c-myc and BCL2 expression, and an increase in cleaved PARP and cleaved caspase-3 expression and chemosensitivity. Taken together, our data suggest that the eIF4E may promote melanoma cell invasion and metastasis, and may also serve as a promising prognostic marker and a potential therapeutic target for melanoma.

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts

Angiopoietin‐like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor‐β and hypoxia‐inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation.

Conversion from Cystine to Noncystine Stones: Incidence and Associated Factors

Purpose: Patients with cystinuria are often treated with medical alkalization and shock wave lithotripsy, although each treatment is hypothesized to increase the risk of calcium phosphate stones. We performed a multicenter retrospective review to evaluate whether stones of another composition develop in patients with cystinuria and with what frequency. Materials and Methods: We retrospectively reviewed the records of a multi‐institutional cohort of patients with cystinuria. We assessed medications, stone analyses, 24‐hour urinalyses and types of procedures. We compared patients who formed only cystine stones vs those with noncystine stones. Results: We identified 125 patients from a total of 5 institutions who were followed a mean of 5.2 years (range 0 to 26). Stones with noncystine components were submitted by 37 patients (29.6%). Potassium citrate medication was not associated with a noncystine composition (p = 0.1877). Regarding surgical management 18 patients (13%) underwent at least 1 shock wave lithotripsy session (range 0 to 9) and 79 (63%) underwent percutaneous nephrolithotomy at least once (range 0 to 10). When stratified based on pure cystine vs converted stones, the average total number of shock wave lithotripsy and percutaneous nephrolithotomy procedures was higher in the group with cystine and subsequent noncystine stone compositions (0.94 vs 0.10, p <0.0001, and 1.7 vs 1.5, p = 0.0053, respectively). On logistic regression male gender (OR 3.1, p = 0.0280) and the number of shock wave lithotripsy sessions (OR 3.0, p = 0.0170) were associated with an increased likelihood of the development of stones with a noncystine composition. Conclusions: Stones with noncystine components develop in more than 25% of patients with cystinuria, underscoring the importance of continued stone analysis. In this study prior shock wave lithotripsy was associated with conversion to a noncystine stone composition while urinary alkalization therapy was not associated.

Abstract 3145: eIF4E, an adverse prognostic marker of melanoma patient survival, increases melanoma cell invasion

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Human cutaneous melanoma is a life-threatening skin cancer due to its invasive nature and high metastatic potential, leading to poor prognosis for melanoma patients. However, the mechanisms for melanoma invasion and metastasis are poorly understood. Human eukaryotic translation initiation factor 4E (eIF4E) has been shown to be associated with tumor progression in multiple cancer types. However, the role of eIF4E in melanoma progression is not very well known. We examined eIF4E expression in 448 melanocytic lesions at different stages using tissue microarray and found that positive eIF4E staining was significantly increased in primary melanomas compared to dysplastic nevi (P<0.001), and further increased in metastatic melanomas compared to primary melanomas (P=0.008). EIF4E expression was correlated with melanoma thickness (P<0.001) and was inversely correlated with overall and disease-specific 5-year survival of all and primary melanoma patients especially those with tumor ≥4mm thick combined with metastatic melanoma patients. Furthermore, positive eIF4E expression was significantly higher in AJCC stage I-II melanomas compared to stage III-IV melanomas. Multivariate Cox regression analysis also revealed that eIF4E is an independent prognostic marker. FACS analysis and sulforhodamine B (SRB) cell proliferation assay showed that eIF4E knockdown in melanoma cells resulted in a significant increase and decrease in apoptosis and cell proliferation, respectively. EIF4E knockdown in melanoma cells also resulted in a down regulation of mesenchymal markers such as vimentin, N-cadherin, α-smooth muscle actin (α-SMA) and the EMT inducing transcription factor Twist. Additionally eIF4E knockdown in melanoma cells led to a decrease in the expression of c-Myc and Bcl2 and an increase in the expression of cleaved PARP and cleaved Caspase3. Moreover, down regulation of eIF4E resulted in a decrease in both melanoma cell invasion and MMP-2 activity. Taken together our data suggests the eIF4E may promote melanoma cell invasion and metastasis by inducing EMT and preventing apoptosis and also by increasing MMP-2 activity. EIF4E may also serve as a promising prognostic marker and a potential therapeutic target for melanoma. Citation Format: Shahram Khosravi, Gholamreza Safaee Ardekani, Magdalena Martinka, Christopher John Ong. eIF4E, an adverse prognostic marker of melanoma patient survival, increases melanoma cell invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3145. doi:10.1158/1538-7445.AM2014-3145