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Wang Y.,Peking University | Radfar S.,Yale University | Liu S.,Dana-Farber Cancer Institute | Riker A.I.,Ochsner Cancer Institute | Khong H.T.,University of South Alabama
BMC Medicine | Year: 2010

Background: Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation.Methods: Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT-PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (pheripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines.Results: A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6- amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other.Conclusion: MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma. © 2010 Wang et al; licensee BioMed Central Ltd. Source


Zhou M.,University of South Alabama | Zhou M.,Central South University | Liu Z.,University of South Alabama | Zhao Y.,University of South Alabama | And 10 more authors.
Journal of Biological Chemistry | Year: 2010

Paclitaxel (Taxol) is an effective chemotherapeutic agent for treatment of cancer patients. Despite impressive initial clinical responses, the majority of patients eventually develop some degree of resistance to Taxol-based therapy. The mechanisms underlying cancer cells resistance to Taxol are not fully understood. MicroRNA (miRNA) has emerged to play important roles in tumorigenesis and drug resistance. However, the interaction between the development of Taxol resistance and miRNA has not been previously explored. In this study we utilized a miRNA array to compare the differentially expressed miRNAs in Taxol-resistant and their Taxol-sensitive parental cells. We verified that miR-125b, miR-221, miR-222, and miR-923 were up-regulated in Taxol-resistant cancer cells by real-time PCR. We further investigated the role and mechanisms of miR-125b in Taxol resistance. We found that miR-125b was up-regulated in Taxol-resistant cells, causing a marked inhibition of Taxol-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to Taxol in cancer cells. Moreover, we demonstrated that the pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) is a direct target of miR-125b. Down-regulation of Bak1 suppressed Taxol-induced apoptosis and led to an increased resistance to Taxol. Restoring Bak1 expression by either miR-125b inhibitor or re-expression of Bak1 in miR-125b-overexpressing cells recovered Taxol sensitivity, overcoming miR-125-mediated Taxol resistance. Taken together, our data strongly support a central role for miR-125b in conferring Taxol resistance through the suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming Taxol resistance in a number of different tumor histologies. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Metge B.J.,University of South Alabama | Liu S.,University of South Alabama | Riker A.I.,Ochsner Cancer Institute | Fodstad O.,University of South Alabama | And 3 more authors.
Oncology | Year: 2010

Objective: Breast cancer metastasis suppressor 1 (BRMS1) has been shown to functionally reduce the metastatic potential of melanoma. We also previously reported that BRMS1 negatively regulates the expression of the oncoprotein osteopontin (OPN). This study was carried out to assess the clinical relevance of BRMS1 and OPN in melanoma. Methods: Epigenetic regulation of BRMS1 was assessed by treating clinically derived melanoma cell lines with the demethylating agent 5-aza-2′-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA), followed by sodium bisulfite modification and methylation-specific PCR. Assessments of BRMS1 and OPN levels were performed using immunoblotting, quantitative real-time RT-PCR or reporter assays. RNA silencing was employed to abrogate the expression of OPN in melanoma-derived cell lines. The in vivo relevance of our findings was determined with experiments using athymic nude mice. Results: The reduced expression of BRMS1 in surgically excised melanoma specimens correlated with increased OPN expression during the progression from primary to metastatic melanoma. Treatment with DAC and TSA elevated BRMS1 levels, but caused an inconsistent change in OPN gene expression. Abrogating the expression of OPN in BRMS1-deficient metastatic melanoma-derived cell lines retarded the growth of melanoma tumor xenografts in athymic nude mice. Conclusion: While treatment with DAC and TSA may not be a universally applicable treatment alternative in melanoma, silencing the expression of OPN in metastatic melanomas that have lost expression of BRMS1 is a potential option for therapeutic intervention. Copyright © 2010 S. Karger AG. Source


Howell Jr. P.M.,University of South Alabama | Li X.,University of South Alabama | Riker A.I.,Ochsner Cancer Institute | Xi Y.,University of South Alabama
Ochsner Journal | Year: 2010

Melanoma is a highly aggressive and deadly skin cancer. Early intervention correlates with nearly 100% patient survival, but greater than 80% mortality is associated with advanced disease. Currently, few treatment options are available for patients with metastatic melanoma, and the global incidence of melanoma is increasing faster than that of other cancers. Therefore, it is vitally important to uncover and use genetic and epigenetic regulatory mechanisms at work during the development and progression of melanoma for better prevention, diagnosis, and clinical management. MicroRNA (miRNA) is a set of small, single-stranded, noncoding RNAs that target the 3'-untranslated region of an estimated 30% of all human genes to inhibit their expression. Our understanding of miRNA-mediated regulation of cancers has grown immensely over the past decade. Here we review currently available data on melanoma-associated miRNAs, highlighting those deregulated miRNAs targeting important genes and signaling pathways involved in the progression of melanocytes to primary and metastatic melanoma. Understanding the important roles of miRNAs in melanoma progression and metastasis development will contribute to the development of miRNA-targeted therapy in the future. © Academic Division of Ochsner Clinic Foundation. Source


Marcus J.D.,Ochsner Cancer Institute | Mott F.E.,Georgia Regents University
Ochsner Journal | Year: 2014

Background: Communication is the cornerstone of good multidisciplinary medical care, and the impact of conversations about diagnosis, treatment, and prognosis is indisputable. Healthcare providers must be able to have difficult conversations that accurately describe diagnostic procedures, treatment goals, and the benefits and/or risks involved.Methods: This paper reviews the literature about the importance of communication in delivering bad news, the status of communication training, communication strategies, and psychosocial interventions.Results: Although many published guidelines address difficult communication, communication training is lacking. Consequently, many clinicians may have difficulties with, or in the worst-case scenario, avoid delivering bad news and discussing end-of-life treatment. Clinicians also struggle with how to have the last conversation with a patient and how to support patient autonomy when they disagree with a patient’s choices.Conclusion: There is a clinical imperative to educate physicians and other healthcare workers on how to effectively deliver information about a patient’s health status, diagnostic avenues to be explored, and decisions to be made at critical health junctions. Knowing how to implement the most rudimentary techniques of motivational interviewing, solutionfocused brief therapy, and cognitive behavioral therapy can help physicians facilitate conversations of the most difficult type to generate positive change in patients and families and to help them make decisions that minimize end-of-life distress. © 2014, Academic Division of Ochsner Clinic Foundation. Source

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