The Role of hnRNP L in Non-Small Cell Lung Cancer

hnRNP L 在非小细胞肺癌中的作用

• 批准号: 9177289
• 负责人: Margaret Amy Park
• 金额: $ 16.58万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177289
• 关键词: Accounting; Address; Anchorage-Independent Growth; Applications Grants; Binding; Biological; Biological Assay; CASP9 gene; Cancer Model; Caspase; Cause of Death; Cell Survival; Cells; Cessation of life; Clinical; Colorectal Cancer; Data; Developed Countries; Development; Disease; Distal; Down-Regulation; Elements; Epithelial Cells; Event; Foundations; Future; Goals; Heterogeneous-Nuclear Ribonucleoprotein L; Human; Indium; Individual; Investigation; Laboratories; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Molecular; Molecular Target; Non-Small-Cell Lung Carcinoma; Oncogenic; Pathway interactions; Patients; Phenotype; Phosphorylation; Protein Isoforms; Purines; RNA; RNA Recognition Motif; RNA Sequences; RNA Splicing; Radiation; Reporting; Role; Severity of illness; Signal Transduction; Small Interfering RNA; Specificity; Survival Rate; Therapeutic; Tumorigenicity; United States; Unresectable; Validation; Woman; Xenograft Model; anti-cancer therapeutic; base; cancer cell; cell transformation; chemotherapy; combat; improved; in vivo; mRNA Precursor; malignant breast neoplasm; men; mutant; next generation; novel; novel therapeutics; outcome forecast; palliative; small hairpin RNA; success; transcriptome sequencing; tumor; tumorigenic

Lung cancer is the leading cause of death of both men and women in industrialized countries, accounting for an estimated 28% of all cancer deaths in the United States. Non-small cell lung cancers (NSCLC) represent the majority of lung cancers and carry a poor prognosis with a median survival of less than 12 months. Most patients present with unresectable disease, and the current treatment options of chemotherapy and radiation are palliative at best. Therefore, new strategies are needed in the treatment of NSCLC in order to impact the severity of this disease. In this study, we are focusing on NSCLC models for examining distal signaling mechanisms that modulate the development and maintenance of NSCLC cells/tumors. Specifically, this grant application focuses on the RNA splicing events regulated by the phosphorylation/activation of the RNA trans-factor, hnRNP L, which occurs only in transformed cells. In stark contrast with our findings on the phosphorylation of Ser52 in hnRNP L in transformed cells, downregulation of hnRNP L in non-transformed cells had no effect on RNA splicing events important in maintaining oncogenic phenotypes (e.g. anchorage-independent growth (AIG)). Further investigations by our laboratory determined that the lack of effect on RNA splicing events in non-transformed cells was due to a lack of phosphorylation of Ser52 in hnRNP L. Thus, these findings suggest that the phosphorylation of hnRNP L (i.e. activation in transformed cells) mediates specific RNA splicing events important in cell survival, proliferation, and AIG versus constitutive functions of non-phosphorylated hnRNP L. Therefore, we hypothesize that the phosphorylation of hnRNP L on Ser52 is required for modulating a specific subset of splicing events, which are important for NSCLC cells to develop and maintain transformed phenotypes. The proposed studies in this application serve to determine the specific “cluster” of RNA splicing events regulated by the phosphorylation of hnRNP L. Once identified, we will further investigate the biological relevance of these RNA splicing events in maintaining the oncogenic phenotypes of NSCLC cells. The key mechanisms being examined in this grant application are specific to transformed cells, translatable to >70% of NSCLCs, and at an extreme distal point in oncogenic pathways. Therefore, these distal mechanisms are plausible and highly desired targets for the development of new anti-cancer therapeutics.

肺癌是工业化国家男性和女性死亡的主要原因 据估计，美国癌症死亡人数占 28%。非小细胞肺癌（NSCLC）代表 大多数肺癌的预后较差，中位生存期不到 12 个月。最多 患者患有无法切除的疾病，目前的治疗选择是化疗和放疗 充其量只是姑息治疗。因此，非小细胞肺癌的治疗需要新的策略，以影响其严重程度 这种疾病。在这项研究中，我们重点关注 NSCLC 模型，以检查远端信号传导机制 调节 NSCLC 细胞/肿瘤的发育和维持。具体来说，本次拨款申请重点 关于由RNA反式因子hnRNP L的磷酸化/激活调节的RNA剪接事件， 仅发生在转化细胞中。与我们对 hnRNP L 中 Ser52 磷酸化的发现形成鲜明对比 转化细胞中，非转化细胞中 hnRNP L 的下调对 RNA 剪接事件没有影响 对于维持致癌表型（例如锚定非依赖性生长（AIG））很重要。更远 我们实验室的研究确定，对非转化细胞中的 RNA 剪接事件缺乏影响 是由于 hnRNP L 中 Ser52 缺乏磷酸化所致。因此，这些发现表明磷酸化 hnRNP L（即转化细胞中的激活）介导对细胞存活很重要的特定 RNA 剪接事件， 增殖，以及 AIG 与非磷酸化 hnRNP L 的组成功能。因此，我们假设 hnRNP L 在 Ser52 上的磷酸化是调节剪接事件的特定子集所必需的，这 对于 NSCLC 细胞发展和维持转化表型很重要。本研究中提出的研究 应用程序用于确定受磷酸化调节的RNA剪接事件的特定“簇” hnRNP L。一旦确定，我们将进一步研究这些 RNA 剪接事件的生物学相关性 维持 NSCLC 细胞的致癌表型。本次拨款正在研究的关键机制 应用程序对转化细胞具有特异性，可转化为 > 70% 的 NSCLC，并且位于最远端 致癌途径。因此，这些远端机制是合理且高度期望的目标 开发新的抗癌疗法。