UBQLN1在乳腺癌恶病质相关脂肪丢失中的作用与机制研究

Cancer cachexia is an energy-wasting syndrome that affects approximately 50-80% of patients with advanced cancer, and that is closely related to poor prognosis, accounting for about 20% of cancer deaths. It is characterized by the loss of skeletal muscle and adipose tissue,leading to substantialweight loss. However, its pathogenesis remains poorly understood. Based on the previous research, preliminary results and the literatures, the applicant hypothesizes that the exosome-derived miR-155 from breast cancer cell targets ubiquilin 1 (UBQLN1) in adipocytes, leading to the impairments of proteasome and autophagy, and activation of protein kinase A (PKA), and subsequent cancer cachexia-related changes of the structure and function of adipocytes. The subject aims to elucidate, from different aspects such as clinical studies, animal studies, and cell culturing, 1) the role of UBQLN1 in adipocyte differentiation and fat lossin the cancer cachexia and its underlying mechanism, particularly its signaling transduction or pathways; 2) the possibility of miR-155/UBQLN1 as biomarkers for the diagnosis and treatment of the cancer cachexia in the patientswith breast cancer. The potential results will provide a new theoretical explanation for the occurrence and development of the cancer cachexia, and may also provide new biomarkers and novel targeted therapies for the cancer cachexia.

癌症恶病质是一种能量消耗性综合征，影响约50-80％的晚期癌症患者，与不良预后密切相关，大约占癌症死亡人数的20％左右，其典型特征是因骨骼肌和脂肪组织的丢失导致体重减轻，但其发病机制仍有待深入研究。申请者在前期研究基础上，结合预实验结果和文献资料，提出如下假说：乳腺癌细胞外泌体来源的miR-155作用于脂肪细胞的UBQLN1，导致脂肪细胞蛋白酶体、细胞自噬、PKA活性的变化，并由此引发癌症恶病质相关的脂肪丢失。课题将从临床、实验动物、细胞培养等不同层面，阐明：1）UBQLN1在癌症恶病质时脂肪细胞分化，以及脂肪丢失中的作用与机制，尤其是其信号转导途径；2）miR-155/UBQLN1作为乳腺癌恶病质诊断和治疗标志物的可行性。其研究成果将为癌症恶病质的发生、发展提出新的理论解释，并可能为其诊断提供新的标志物，为其治疗提供新的作用靶点。

癌症恶病质是一种能量消耗性综合征，影响约50-80％的晚期癌症患者，与不良预后密切相关，大约占癌症死亡人数的20％左右，其典型特征是因骨骼肌和脂肪组织的丢失导致体重减轻，但其发病机制仍有待深入研究。申请者在前期研究基础上，结合预实验结果和文献资料，提出如下假说：乳腺癌细胞外泌体来源的miR-155作用于脂肪细胞的UBQLN1，导致脂肪细胞蛋白酶体、细胞自噬、PKA活性的变化，并由此引发癌症恶病质相关的脂肪丢失。课题将从临床、实验动物、细胞培养等不同层面，阐明：1）UBQLN1在癌症恶病质时脂肪细胞分化，以及脂肪丢失中的作用与机制，尤其是其信号转导途径；2）miR-155/UBQLN1作为乳腺癌恶病质诊断和治疗标志物的可行性。其研究成果将为癌症恶病质的发生、发展提出新的理论解释，并可能为其诊断提供新的标志物，为其治疗提供新的作用靶点。