PO.TB03.03 · 肿瘤生物学
研究应激诱导的SIPA1核内重定位在乳腺癌转移中的作用
Investigating the role of stress induced nuclear relocalization of SIPA1 in breast cancer metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是美国女性中最常被确诊的癌症，而转移是乳腺癌患者死亡的主要原因。该疾病在局部肿瘤中的5年（2015-2021年）生存率为87.2%，但在已转移的癌症中降至32.6%。因此，Hunter实验室的目标是通过鉴定转移机制来理解癌症进展的动态过程。在本研究中，我们假设当乳腺癌细胞在转移过程中处于应激状态时，转移易感性蛋白向细胞核的重定位对于转移进展至关重要。实验室先前的工作揭示，转移易感性基因存在于核仁——一个中央应激感受器中。在应激期间，细胞质蛋白被隔离于核仁中，且核仁的体积增大。我们发现SIPA1（信号诱导的增殖相关蛋白1），实验室最早鉴定的转移易感性基因之一，在模拟转移的应激下重定位至细胞核。SIPA1是一种有丝分裂原诱导的GTP酶激活蛋白，主要已知存在于核周区域。然而，SIPA1可重定位至细胞核，这一表型与乳腺癌患者的不良预后相关。在当前实验中，我们观察到SIPA1响应热休克、营养剥夺、缺氧和低剂量化疗药物等应激条件而重定位至细胞核。这种应激诱导的重定位主要位于核斑点（一个剪接因子储存位点），部分位于核仁。此外，SIPA1还结合于多条染色体着丝粒区域附近的高阶重复序列。通过光谱核型分析，我们观察到在乳腺上皮细胞中敲低SIPA1会改变染色体稳定性。未来的实验包括测定应激下SIPA1核内重定位机制的试验，以及鉴定SIPA1邻近区域相互作用蛋白的邻近标记试验。揭示控制SIPA1在细胞核内重定位的机制，将进一步阐明乳腺癌细胞在转移过程中负责应激反应的通路。
查看英文原文 English abstract
Breast cancer is the most commonly diagnosed cancer among women in the U.S., and metastasis is the leading cause of deaths in breast cancer patients. This disease presents with an 87.2% 5-year (2015-2021) survival rate in regional tumors which drops to 32.6 % in metastasized cancers. The goal of Hunter laboratory is therefore to understand the dynamics of cancer progression by identifying mechanisms of metastasis. In this study, we hypothesize that when breast cancer cells are under stress during metastasis, the relocalization of metastasis susceptibility proteins to the nucleus is essential for metastatic progression. Previous work in the laboratory revealed that metastasis susceptibility genes were present in the nucleolus, a central stress sensor. During stress, cytoplasmic proteins are sequestered in the nucleolus and the size of the nucleolus increases. We showed that SIPA1 (Signal Induced Proliferation-associated 1), one of the first metastasis susceptibility genes identified in the laboratory, relocalizes to the nucleus under stresses mimicking metastasis. SIPA1 is a mitogen-induced GTPase activating protein predominantly known to be present in the perinuclear region. However, SIPA1 can relocalize to the nucleus, a phenotype associated with poor prognosis in breast cancer patients. In current experiments, we observed that SIPA1 relocalizes to the nucleus in response to stress conditions like heat shock, nutrient deprivation, hypoxia and low dose chemotherapy drugs. This stress-induced relocalization is primarily in nuclear speckles, a splicing factor storage site, and partially in the nucleolus. Additionally, SIPA1 also binds to higher order repeats near the centromeric regions of multiple chromosomes. Through spectral karyotyping, we observed that knocking down SIPA1 in breast epithelial cells alters chromosomal stability. Future experiments involve assays to determine the mechanism of nuclear relocalization of SIPA1 under stress and proximity assays to identify the interacting proteins in the proximity of SIPA1. Revealing mechanisms that control the relocation of SIPA1 in the nucleus, will further clarify the pathways responsible for stress response in breast cancer cells during metastasis.
利益披露 Disclosure
N. S. Kotian, None.