ARID1A通过E-cadherin调控肿瘤细胞迁移、侵袭的功能及分子基础

gene encodes BAF250a protein, a non-catalytic subunit of SWI/SNF chromatin remodeling complex. Recent sequencing studies have revealed that is frequently mutated in a variety of human cancers, including breast cancer. These mutations led to the down-regulation or loss of BAF250a in cancer cells, which was associated with cancer cell proliferation and metastasis. This gene is a novel tumor suppressor of great interest. However, the underlying mechanism of in suppression of metastasis remains largely unknown. Previously, we have reported that loss of regulated gastric cancer cell migration and invasion by downregulating E-cadherin and inducing a translocation of b-catenin into the nucleus to promote cancer progress. Whereas in breast cancer cells, we found that loss of increased cell migration and invasion by upregulating E-cadherin and b-catenin, which indicating a novel modulation mechanism of for cancer metastasis. Based on these observations and literatures, we hypothesize that silencing would upregulate the expression of the cytoplasmic fragment of E-cadherin derived from enzyme digestion. The C-terminal fragment of E-cadherin might bind b-catenin and inhibit the proteasome-dependent degradation of b-catenin. Consequently, b-catenin would become more stable and translocate into the nucleus, where it will regulate downstream target gene transcription and promote metastasis. In current study, based on the previous analyses, we will further investigate the functional role and the molecular mechanism of in the modulation of the migration and invasion of breast cancer cells through the E-cadherin and b-catenin pathway using both in vitro and in vivo experiments. Our study will provide novel and fundamental rationale for the clinical diagnosis and treatment of breast cancer.

基因编码蛋白，是SWI/SNF染色质重塑复合物的非催化亚基。最新测序研究发现其在多种肿瘤包括乳腺癌中突变并导致表达缺失或下调，与肿瘤细胞增殖及转移相关，是一个新的热点抑癌基因。但对其抑制肿瘤转移的分子机制了解非常少。本课题组曾报道缺失调控胃癌细胞迁移和侵袭并下调E-钙粘蛋白，促进beta-连环蛋白入核发挥促癌作用。但在乳腺癌细胞中，缺失上调E-钙粘蛋白和连环蛋白并促迁移和侵袭，表明存在新的调控机制。根据预实验及文献分析，推测E-钙粘蛋白胞内剪切片段上调，与连环蛋白结合后抑制了后者通过蛋白酶体的降解过程，从而使连环蛋白上调并入核，调控下游基因转录、促进转移。本研究基于前期研究基础，进一步通过体外分子细胞生物学及体内动物实验，研究并揭示通过E-钙粘蛋白和连环蛋白调控乳腺癌细胞迁移/侵袭的功能和分子机理，为乳腺癌的诊治提供新的理论基础。

ARID1A在肿瘤转移中的作用机制有待研究。我们发现ARID1A在乳腺癌中下调，与预后不良相关。ARID1A沉默促进乳腺癌细胞增殖、移行、侵袭以及体内的转移（小鼠和斑马鱼），同时上调E-cadherin/CDH1，这是一个转移的抑制分子。ARID1A靶向CDH1基因的第2个外显子，排除RNA聚合酶II以负调控CDH1的表达。ARID1A沉默上调E-cadherin切割相关的酶，特别是基质金属蛋白酶MMP，促进产生E-cadherin的C端片段(CTFs)。E-cadherin/CTF2结合b-catenin，排除了b-catenin降解复合物与b-catenin的结合，从而稳定了b-catenin。ARID1A沉默和E-cadherin/CTF2的过表达激活了b-catenin信号传导，促进乳腺癌细胞移行、侵袭以及体内的转移（斑马鱼和裸鼠）。MMP抑制剂GM6001和BB94以及b-catenin的抑制剂ICG-001抑制ARID1A缺失的乳腺癌细胞的移行和侵袭。我们的发现为了解ARID1A在转移中的机制提供了新的见解，为靶向治疗ARID1A缺失的乳腺癌提供了科学依据。