The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis

Riker, Adam I.; Enkemann, Steven A.; Fodstad, Øystein; Liu, Suhu; Ren, Shengxiang; Morris, Christopher G.; Xi, Yaguang; Howell, Paul; Metge, Brandon J.; Samant, Rajeev S.; Shevde, Lalita A.; Li, Wenbin; Eschrich, Steven; Daud, Adil; Ju, Jingfang; Matta, Jaime

doi:10.1186/1755-8794-1-13

Cited by 444 publications

(470 citation statements)

References 54 publications

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“…It has also been seen to protect against growth factor withdrawal-induced apoptosis in myeloid precursor cells, and surprisingly to allow differentiation of these cells, whereas Bcl-2 had an anti-proliferative function 388 . Bfl-1 is also seen overexpressed in solid tumours, such as stomach cancer 369 , breast cancer 389 , and metastatic melanoma 368 . It also appears to regulate hypoxia-induced apoptosis and oxidant-induced necrosis of epithelial cells in culture 390 , presenting an opportunity for drug studies targeting Bfl-1 in hyperoxic acute lung injury (HALI) in addition to haematological malignancies and solid tumours.…”

Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…The gene encoding human Gpr19 resides on the short arm of chromosome 12 in a region that is frequently rearranged in childhood leukemia and to a lesser extent in other neoplasms; accordingly, GPR19 has been postulated to play a role in cancer development (39). In fact, high levels of mRNA coding for GPR19 were found in metastatic melanoma (7,40). Here we showed that GPR19 is associated with lung cancer.…”

Section: Discussionmentioning

confidence: 60%

Expression of G Protein-Coupled Receptor 19 in Human Lung Cancer Cells Is Triggered by Entry into S-Phase and Supports G2–M Cell-Cycle Progression

Kastner

Voss

Keuerleber

et al. 2012

Molecular Cancer Research

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It has long been known that G protein-coupled receptors (GPCR) are subject to illegitimate expression in tumor cells. Presumably, hijacking the normal physiologic functions of GPCRs contributes to all biologic capabilities acquired during tumorigenesis. Here, we searched for GPCRs that were expressed in lung cancer: the mRNA encoding orphan G protein-coupled receptor 19 (GPR19) was found frequently overexpressed in tissue samples obtained from patients with small cell lung cancer. Several observations indicate that overexpression of Gpr19 confers a specific advantage to lung cancer cells by accelerating transition through the cellcycle. (i) Knockdown of Gpr19 mRNA by RNA interference reduced cell growth of human lung cancer cell lines. (ii) Cell-cycle progression through G 2 -M-phase was impaired in cells transfected with siRNAs directed against Gpr19 and this was associated with increased protein levels of cyclin B1 and phosphorylated histone H3. (iii) The expression levels of Gpr19 mRNA varied along the cell-cycle with a peak observed in S-phase. (iv) The putative control of Gpr19 expression by E2F transcription factors was verified by chromatin immunoprecipitation: antibodies directed against E2F-1 to -4 allowed for the recovery of the Gpr19 promoter. (v) Removal of E2F binding sites in the Gpr19 promoter diminished the expression of a luciferase reporter.

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“…Previous gene expression studies of melanocytic tumors also reported that the predominant change was decreased expression of genes in advanced malignancy. 14,15 Among genes that were decreased (Table 2b), SFN showed the greatest and most significant decrease. Stratifin is a protein that was initially identified in keratinizing stratified squamous epithelium and has a regulatory role in the G2/M cell cycle check point and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…However, several prior studies of gene expression have reported downregulation of keratinocyte-related proteins, such as keratins, associated with melanoma. [14][15][16] Others have encountered an increase in keratin genes in advanced melanoma. 23 Unexpectedly high expression of keratin-associated proteins in primary/early stage melanomas relative to metastases has been a matter of considerable concern to previous investigators.…”

Section: Discussionmentioning

confidence: 99%

“…Others, using cell lines or tissue samples, have studied DNA expression profiling of normal melanocytes, nevi, primary melanomas, and regional and distant metastases. [7][8][9][10][11][12][13][14][15][16][17][18][19] Conway et al 19 used the cDNA-mediated annealing, selection, extension, and ligation assay to evaluate formalin-fixed, paraffin-embedded archival primary melanoma specimens, and reported osteopontin overexpression as a potential prognostic biomarker. Rangel et al, 20 using immunohistochemistry, had previously shown that overexpression of osteopontin, correlated with the likelihood of sentinel lymph node metastasis.…”

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confidence: 99%

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Differential gene expression profiling of primary cutaneous melanoma and sentinel lymph node metastases

Koh

Wei

et al. 2012

Modern Pathology

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Limited understanding of molecular mechanisms of metastasis in melanoma contributes to the absence of effective treatments. Increased knowledge of alterations in genes that underpin critical molecular events that lead to metastasis is essential. We have investigated the gene expression profiles of primary melanomas and melanoma metastases in sentinel lymph nodes. A total of 19 samples (10 primary melanomas and 9 sentinel lymph node metastases) were evaluated. Melanoma cells were dissected from tissue blocks. Total mRNA was isolated, amplified, and labeled using an Ambion Recover All Total Nucleic Acid Isolation kit, Nu-GEN WTOvation formalin-fixed, paraffin-embedded RNA Amplification System, and FL-Ovation cDNA Biotin Module V2, respectively. Samples were hybridized to the Affymetrix Gene Chip Human U133 Plus 2.0 Array. Data were analyzed using Partek Genomics Suite Version 6.4. Genes selected showed Z2-fold difference in expression and Po5.00EÀ2. Validation studies used standard immunohistochemical assays. Hierarchical clustering disclosed two distinct groups: 10 primary melanomas and 9 sentinel lymph node metastases. Gene expression analysis identified 576 genes that showed significant differential expression. Most differences reflected decreased gene expression in metastases relative to primaries. Reduced gene expression in primaries was less frequent and less dramatic. Genes significantly increased or decreased in sentinel lymph node metastases were active in cell adhesion/structural integrity, tumor suppression, cell cycle regulation, and apoptosis. Validation studies indicate that MAGEC1 (melanoma antigen family C1) and FCRL1 (Fc receptor-like 1) are involved in melanoma progression. There are striking differential gene expression patterns between primary and nodally metastatic melanomas. Similar findings were seen with autologous paired primary melanomas and sentinel lymph node metastases, supporting involvement of these gene alterations in evolution of metastases. With further study, it may be possible to determine the exact sequence of molecular events that underlie melanoma metastases.

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The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis

Cited by 444 publications

References 54 publications

Role of the pro-survival molecule Bfl-1 in melanoma

Role of the pro-survival molecule Bfl-1 in melanoma

Expression of G Protein-Coupled Receptor 19 in Human Lung Cancer Cells Is Triggered by Entry into S-Phase and Supports G2–M Cell-Cycle Progression

Differential gene expression profiling of primary cutaneous melanoma and sentinel lymph node metastases

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