THE ROLE OF MALT1 IN MELANOMA GROWTH AND METASTASIS

 描述（由申请人提供）：paracaspase MALT 1（粘膜相关淋巴瘤易位1基因）在淋巴瘤中经常被激活。它通过对包括CYLD、A20、RelB和Bcl 10在内的少数底物进行序列特异性蛋白水解，作为NF-κ B和JNK信号通路的激活剂发挥作用。用具有医学活性的吩噻嗪化合物抑制MALT 1已被证明对治愈最具侵袭性和其他不可治疗的B细胞淋巴瘤非常有效。迄今为止，人们对MALT 1在其他实体癌（如黑色素瘤）中的作用知之甚少，尽管最近在免疫疗法或BRAF600 E/MEK癌基因靶向疗法方面取得了进展，但黑色素瘤仍然是最致命的皮肤癌形式。本研究的目的是探讨MALT 1及其下游靶点在黑色素瘤生长和转移中的作用。为此，我们的初步研究已经证明，CYLD，MALT 1的潜在靶标，在转移性黑色素瘤细胞中显著降低，并且CYLD的强制表达通过抑制NF-κ B和JNK信号通路来抑制黑色素瘤生长和转移。相反，与正常和放射状生长期黑素瘤细胞相比，MALT 1在转移性和垂直生长期黑素瘤细胞中显著增加。转移性人黑色素瘤细胞系A2058中MALT 1的shRNA介导的基因沉默在体外和体内均减缓细胞生长，并抑制体内转移。基于这些发现，我们假设MALT 1在黑色素瘤生长和转移中具有重要作用，并且是联合治疗的潜在靶点。这一假设将在两个单独的目标中进行检验。目的研究MALT 1及其下游靶基因在黑色素瘤生长、生存和转移中的作用。目的II是确定遗传MALT 1抑制对BRAF600 E/MEK靶向治疗的影响。我们相信，这项研究的结果将导致更好地了解黑色素瘤的发病机制，并提供见解的治疗策略，可转化为临床应用。

 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.