Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression

Kono, Michihiro; Dunn, Ian S.; Durda, Paul J.; Butera, David; Rose, Lenora B.; Haggerty, Timothy J.; Benson, Elizabeth M.; Kurnick, James T.

doi:10.1158/1541-7786.mcr-06-0077

Cited by 135 publications

(130 citation statements)

References 59 publications

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“…3). These results are consistent with other work implicating MITF in melanoma survival (Haq et al 2013) 754 Genome Research www.genome.org therefore regulates two contrary effects of BRAF inhibition, namely, induction of melanocyte differentiation, which is an anti-tumorigenic effect important for immune cell recognition of melanoma (Kono et al 2006;Boni et al 2010;Liu et al 2013), and the pro-tumorigenic effect of engaging innate drug resistance to BRAF inhibition.…”

Section: Resultssupporting

confidence: 90%

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

et al. 2014

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Thousands of putative enhancers are characterized in the human genome, yet few have been shown to have a functional role in cancer progression. Inhibiting oncokinases, such as EGFR, ALK, ERBB2, and BRAF, is a mainstay of current cancer therapy but is hindered by innate drug resistance mediated by up-regulation of the HGF receptor, MET. The mechanisms mediating such genomic responses to targeted therapy are unknown. Here, we identify lineage-specific enhancers at the MET locus for multiple common tumor types, including a melanoma lineage-specific enhancer 63 kb downstream from the MET TSS. This enhancer displays inducible chromatin looping with the MET promoter to up-regulate MET expression upon BRAF inhibition. Epigenomic analysis demonstrated that the melanocyte-specific transcription factor, MITF, mediates this enhancer function. Targeted genomic deletion (<7 bp) of the MITF motif within the MET enhancer suppressed inducible chromatin looping and innate drug resistance, while maintaining MITF-dependent, inhibitor-induced melanoma cell differentiation. Epigenomic analysis can thus guide functional disruption of regulatory DNA to decouple pro-and antioncogenic functions of a dominant transcription factor and block innate resistance to oncokinase therapy.

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Section: Resultssupporting

confidence: 90%

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

et al. 2014

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“…39 In vitro, these inhibitors consistently enhance MLANA or SILV transcript levels, as reported for 70% of the melanoma cell lines treated with the ERK inhibitors PD98059 and U0126. 40 We found that in the LB2259-MEL human melanoma cells, the repressive effect of IL-1b on MITF-M expression was dependent on both NF-jB and JNK activation. MITF-M downregulation induced by IL1b was not mediated by ERK activation, because we found that inhibitors PD98059 and U0126 did not counteract this effect (data not shown).…”

Section: Tumor Immunologymentioning

confidence: 73%

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

Kholmanskikh

Baren

Brasseur

et al. 2010

Intl Journal of Cancer

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We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4-to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1b. This effect is NF-jB and JNKdependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1b reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1a or IL-1b secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that~13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.

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“…Microphthalmia transcription factor-M (MITF-M), a melanocyte-specific master transcription factor, may also regulate MART-1 expression. 29,30 Reduced expression of MITF-M is associated with lack of MART-1 expression by melanoma cells. In our study, a melanoma that was negative for MART-1 and TRP-2 by IHC had evidence of MART-1 mRNA and TRP-2 mRNA in melanoma cells at the dermo-epidermal junction and in the superficial papillary dermis, but not in the deep dermis.…”

Section: Discussionmentioning

confidence: 99%

RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi

et al. 2008

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Melanoma antigen recognized by T cells 1 (MART-1) and tyrosinase-related protein-2 (TRP-2) are two useful markers for immunohistochemical detection of melanocytic tumors. However, these markers may be passively acquired (phagocytosed) rather than actively synthesized. Reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) can amplify even small amounts of specific mRNA in cells and therefore confirm the cellular source of a marker. We developed a one-step RT in situ PCR procedure in which Thermus thermophilus DNA polymerase synthesizes and amplifies cDNA from mRNA in a single reaction mixture. To examine its practicability and feasibility with formalin-fixed, paraffin-embedded (FFPE) tissue, we compared the results of one-step RT in situ PCR with those of immunohistochemistry (IHC). MART-1 mRNA was identified in the cytoplasm of lesional cells from 23/26 primary melanomas (92%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). MART-1 epitope was detected by IHC in 23/24 primary melanomas (96%), 9/9 metastatic melanomas (100%) and 5/6 nevi (83%). TRP-2 mRNA was identified in the cytoplasm of lesional cells from 17/26 primary melanomas (65%), 6/9 metastatic melanomas (67%) and 4/6 nevi (67%). TRP-2 epitope was detected by IHC in 20/ 24 primary melanomas (83%), 9/9 metastatic melanomas (100%) and 4/6 nevi (67%). Both techniques detected MART-1 and TRP-2 in FFPE melanoma cell lines. Neither marker was detected in squamous cell carcinomas or basal cell carcinomas by RT in situ PCR or IHC. We conclude that the RT in situ PCR technique can be successfully applied to FFPE tissue to determine the cellular sources of gene expression observed by conventional PCR approaches.

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Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression

Cited by 135 publications

References 59 publications

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

Enhancer-targeted genome editing selectively blocks innate resistance to oncokinase inhibition

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

RT in situ PCR detection of MART-1 and TRP-2 mRNA in formalin-fixed, paraffin-embedded tissues of melanoma and nevi

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