THE ROLE OF MALT1 IN MELANOMA GROWTH AND METASTASIS

 描述(申请人提供)：副天冬氨酸氨基转移酶MALT1(粘膜相关淋巴瘤易位1基因)在淋巴瘤中经常被激活。它通过对几种底物包括κ、A20、RemB和Bcl10进行序列特异性的蛋白分解，作为NF-JNKB和JNK2信号通路的激活剂。用具有药物活性的吩噻嗪化合物抑制MALT1已被证明对治愈最具侵袭性和无法治疗的B细胞淋巴瘤非常有效。到目前为止，人们对MALT1在黑色素瘤等其他实体癌症中的作用知之甚少。尽管最近在免疫治疗或BRAF600E/MEK癌基因靶向治疗方面取得了进展，但MALT1仍然是最致命的皮肤癌形式。本研究的目的是探索MALT1及其下游靶点在黑色素瘤生长和转移中的作用。为此，我们的初步研究表明，MALT1的潜在靶点CyLD在转移性黑色素瘤细胞中显著减少，并且强制表达CyLD通过抑制NF-κB和JNK信号通路来抑制黑色素瘤的生长和转移。相反，在转移期和垂直生长期黑色素瘤细胞中，MALT1与正常和放射状生长期黑色素瘤细胞相比显著增加。在转移性人类黑色素瘤细胞系A2058中，shRNA介导的MALT1基因沉默在体外和体内都减缓了细胞的生长，并抑制了体内的转移。基于这些发现，我们假设MALT1在黑色素瘤的生长和转移中具有重要作用，是联合治疗的潜在靶点。这一假设将在两个不同的目标中得到检验。目的研究MALT1及其下游靶点在黑色素瘤生长、存活和转移中的作用。目的II确定MALT1基因抑制对BRAF600E/MEK靶向治疗的影响。我们相信，这项研究的发现将有助于更好地从机制上理解黑色素瘤的发病机制，并为可能转化为临床应用的治疗策略提供见解。

 DESCRIPTION (provided by applicant): The paracaspase MALT1 (Mucosa Associated Lymphoma Translocation 1 gene) is frequently activated in lymphoma. It functions as an activator of the NF-κB and JNK signaling pathways through sequence-specific proteolysis of a handful of substrates including CYLD, A20, RelB and Bcl10. Inhibition of MALT1 with the medicinally active phenothiazine compounds has proven to be very effective for the cure of the most aggressive and otherwise untreatable B-cell lymphoma. To date, little is understood about the role of MALT1 in other solid cancers such as melanoma which, despite recent advances in immunotherapy or BRAF600E/MEK oncogene-targeted therapies, continues to be the most deadly form of skin cancer. The goal of this study is to explore the role of MALT1 and its downstream targets in melanoma growth and metastasis. Towards this end, our preliminary studies have demonstrated that CYLD, a potential target of MALT1, is significantly reduced in metastatic melanoma cells, and that forced expression of CYLD inhibits melanoma growth and metastasis through the suppression of the NF-κB and JNK signaling pathways. In contrast, MALT1 is significantly increased in metastatic and vertical growth phase melanoma cells as compared to normal and radial growth phase melanoma cells. ShRNA-mediated gene silencing of MALT1 in a metastatic human melanoma cell line A2058 slows cell growth both in vitro and in vivo, and inhibits metastasis in vivo. Based on these findings, we hypothesize that MALT1 has an important role in melanoma growth and metastasis and is a potential target for combination therapies. This hypothesis will be tested in two separate Aims. Aim I is to determine the role of MALT1 and its downstream targets in melanoma growth, survival and metastasis. Aim II is to determine the effects of genetic MALT1-inhibition on BRAF600E/MEK-targeted therapies. We believe that findings of this study will lead to a better mechanistic understanding of melanoma pathogenesis, and provide insights to therapeutic strategies that may be translated into clinical applications.