KIT Is a Frequent Target for Epigenetic Silencing in Cutaneous Melanoma

Dahl, Christina; Abildgaard, Cecilie; Riber-Hansen, Rikke; Steiniche, Torben; Lade-Keller, Johanne; Guldberg, Per

doi:10.1038/jid.2014.372

Cited by 43 publications

(49 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…c-KIT mutations can activate the signal transduction cascades that regulate cell proliferation, apoptosis, chemotaxis and adhesion [25]. In GIST tumors, activating mutations of c-KIT were detected, but also the loss or down-regulation of the c-KIT can be observed linked to neoplastic transformation as for example in breast carcinoma and melanoma [11, 12]. Few and dated studies have analyzed c-KIT expression profiles in thyroid tumors [13–16], finding a correlation with differentiation and growth control of thyroid epithelium and also suggesting a c-KIT loss of function in malignant transformation.…”

Section: Discussionmentioning

confidence: 99%

“…There are papers showing that c-KIT is highly expressed or mutated in small cell lung cancer [7], leukemia cells [8], colon cancer [9] and neuroblastoma [10]. On the other hand, c-KIT expression is lost in breast cancer [11] and melanoma [12]. Some studies investigated c-KIT expression in thyroid gland and in thyroid malignancies [13–16], suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and that this function may be lost following malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Loss of c-KIT expression in thyroid cancer cells

et al. 2017

View full text Add to dashboard Cite

Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of c-KIT expression in thyroid cancer cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Paradoxically, KIT expression is either low or undetectable in this latter category of melanomas, which are primarily driven by either BRAF or NRAS activating mutations (11–13). The loss of KIT expression has been attributed to frequent deletion or hypermethylation of the KIT locus in melanoma (14,15). While the loss of KIT in cutaneous melanomas is well documented, it remains unclear whether this loss is a cause or consequence of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling

et al. 2017

View full text Add to dashboard Cite

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF or NRAS activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a kit(lf) mutation into a strain of Tg(mitfa:BRAFV600E); p53(lf) melanoma-prone zebrafish. Melanoma onset was accelerated in kit(lf); Tg(mitfa:BRAFV600E); p53(lf) fish. Tumors from kit(lf) animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAFV600E-mutant human melanoma cell line. We found that pathway stimulation upstream of BRAFV600E could paradoxically reduce signaling downstream of BRAFV600E, and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAFV600E signaling. In vivo, expression of wild-type BRAF delayed melanoma onset, but only in a kit-dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAFV600E-driven melanoma formation.

show abstract

“…Moreover, TYR had many interactions with other DEGs and was a hub node in the PPI network, implying predominant roles in the biological processes of pigmentation. Additionally, the up-regulated KIT , which was previously identified as a oncogenic drivers in sun-impaired skin, was annotated as a potential oncogene in this study [29]. …”

Section: Discussionmentioning

confidence: 99%

Potential molecular characteristics in situ in response to repetitive UVB irradiation

Chen

Zhang

2016

Diagn Pathol

View full text Add to dashboard Cite

BackgroundTo identify molecular characteristics in situ in response to repetitive UVB (ultraviolet-B) irradiation.MethodsMicroarray data from the Gene Expression Omnibus were re-analyzed to identify DEGs (differentially expressed genes) between UVB-irradiated and non-irradiated skin biopsies. Enrichment and annotation analyses were performed respectively using DAVID, and TSGene and TAG databases. PPIs (protein-protein interactions) were analyzed using STRING, and miRNAs (microRNAs) and TFs (transcription factors) were predicted separately by miRNA-related databases and ENCODE. Accordingly, the PPI network and regulatory networks were visualized using Cytoscape, and they were merged together to obtain an integrated network for mining densely connected modules.ResultsAltogether, 151 up- and 64 down-regulated genes were identified between UVB-irradiated and non-irradiated skin biopsies, among which down-regulated DNAJB4 and SLIT2 were annotated as tumor-suppressors and up-regulated KIT was annotated as an oncogene. The up-regulated DEGs were significantly enriched in biological processes related to pigmentation (DCT, SOX10, TYRP1, TYR, MLPH, KIT and GPR143), while the down-regulated DEGs were dramatically related to haemopoiesis and the immune system (GPR183, INHBA, PTPRC, PLEK, CD8A and IKZF1). Furthermore, many miRNAs were screened for the DEGs, including miR-206 and miR-496 targeting KIT, miR-184 targeting DCT, and highly significant miR-337-5p, miR-21 and miR-16. Additionally, TFs were identified for the DEGs, among which PAX5 and HNF4A targeted MLPH and GPR143, respectively, while BATF, SPI1 and EP300 jointly target GPR183, PTPRC and PLEK.ConclusionsThe pigmentation and immune system implicated by DEGs, miRNAs and TFs might be important molecular mechanisms in response to UVB irradiation.

show abstract

KIT Is a Frequent Target for Epigenetic Silencing in Cutaneous Melanoma

Cited by 43 publications

References 41 publications

Loss of c-KIT expression in thyroid cancer cells

Loss of c-KIT expression in thyroid cancer cells

KIT Suppresses BRAFV600E-Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling

Potential molecular characteristics in situ in response to repetitive UVB irradiation

Contact Info

Product

Resources

About