Targeting the let-7-HMGA2 Network in Metastatic Progression in Pancreatic Cancer

描述（由申请人提供）：胰腺导管腺癌（pdac）是一种高致死率的肿瘤，每年在全球范围内造成150万例死亡。大多数患者患有无法手术的转移性疾病，目前尚无有效的治疗方法。因此，迫切需要研究如何确定pdac的进展，以便设计更好的治疗方法。我们正在研究导致PDAC肿瘤进展的分子途径。我们的重点是HMGA2癌基因，它编码HMGA2染色质重塑蛋白。我的实验室发现HMGA2在培养细胞中作为一种强效致癌基因发挥作用，抑制HMGA2的表达可阻断转化表型。我们小组最近发表的研究表明，HMGA2在44%的原发性人pdac中过表达，在侵袭性转移性肿瘤中表达水平最高，但在前体病变或正常胰腺中未表达。此外，我们最近的研究发现HMGA2蛋白水平与分化不良状态和淋巴结转移呈正相关。这些发现强烈提示HMGA2促进PDAC的肿瘤进展，尽管HMGA2功能的分子机制尚不清楚。新出现的证据表明，microRNAs （miRNAs）在肿瘤进展和维持低分化状态中起着关键作用。mirna是一个高度保守的非蛋白质编码小rna家族，可调节互补靶mrna的稳定性或翻译效率。Maitra & Mendell实验室最近的一项研究发现，与正常胰腺细胞相比，侵袭性pdac培养细胞中的肿瘤抑制microrna （TS-miRs）下调，这表明抑制特异性TS-miRs可能促进肿瘤发生。Let-7 mirna是被抑制的mirna之一，并且Let-7在多种肿瘤中作为TS-miR起作用。初步证据还表明let-7抑制HMGA2和其他致癌基因。因此，PDAC中let-7的缺失可能导致致癌蛋白的上调和肿瘤的进展。基于这些发现，我们假设let-7-HMGA2调控环是参与PDAC转移进展的重要途径。我们进一步假设，替换PDAC中的let-7将下调致癌蛋白并阻止肿瘤进展。此外，我们已经开发了一种创新的体内纳米载体递送系统，可以有效地恢复胰腺癌细胞中的let-7 mirna。利用我们独特的资源，我们现在提议用以下具体目标来测试这些假设：定义let-7-HMGA2网络在PDAC中的功能意义，2)在我们的PDAC实验模型中，确定用创新的miRNA纳米载体递送系统替代let-7 TS-miR是否会阻止肿瘤发生和转移进展。这些研究的结果将增强我们对导致胰腺癌进展的分子途径的理解，并为PDAC的miRNA治疗提供新的范例

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinomas (PDACs) are highly lethal tumors accounting for >150,000 deaths worldwide each year. Most patients present with inoperable, metastatic disease for which there are no effective therapies. Thus, research is urgently needed to determine how PDACs progress in order to design better therapies. We are studying the molecular pathways that lead to tumor progression in PDAC. Our focus is the HMGA2 oncogene, which encodes the HMGA2 chromatin remodeling protein. My laboratory discovered that HMGA2 functions as a potent oncogene in cultured cells and inhibiting HMGA2 expression blocks transformation phenotypes. Recently published studies from our group demonstrate that HMGA2 is overexpressed in 44% of primary, human PDACs, with highest levels in invasive, metastatic tumors, but no expression in precursor lesions or normal pancreas. Moreover, our recent study found that HMGA2 protein levels are positively correlated with poor differentiation status and lymph node metastases. These findings strongly suggest that HMGA2 promotes tumor progression in PDAC, although the molecular mechanisms through which HMGA2 functions are unclear. Emerging evidence indicate that microRNAs (miRNAs) play a critical role in tumor progression and maintenance of a poorly differentiated state. miRNAs are a highly conserved family of small, non-protein-coding RNAs that regulate the stability or translation efficiency of complementary target mRNAs. A recent study from the Maitra & Mendell laboratories identified tumor suppressor microRNAs (TS-miRs) that are down-regulated in cultured cells from aggressive PDACs compared to cells from normal pancreas, suggesting that repression of specific TS-miRs could promote tumorigenesis. Let-7 miRNAs were among the repressed miRNAs and let-7 functions as a TS-miR in diverse tumors. Preliminary evidence also indicates that let-7 represses HMGA2 and other oncogenes. Thus, loss of let-7 in PDAC could lead to up-regulation of oncogenic proteins and tumor progression. Based on these findings, we hypothesize that the let-7-HMGA2 regulatory loop is an important pathway involved in metastatic progression in PDAC. We hypothesize further that replacing let-7 in PDAC will down-regulate oncogenic proteins and block tumor progression. Moreover, we have developed an innovative, in vivo nanovector delivery system that effectively restores let-7 miRNAs in pancreatic cancer cells. Using our unique resources, we now propose to test these hypotheses with the following Specific Aims: 1.) Define the functional significance of the let-7-HMGA2 network in PDAC, 2.) Determine if replacing let-7 TS-miR with an innovative miRNA nanovector delivery system blocks tumorigenesis and metastatic progression in our experimental models of PDAC. Results from these studies will enhance our understanding of the molecular pathways that lead to pancreatic cancer progression and should provide a new paradigm for miRNA therapy in PDAC PUBLIC HEALTH RELEVANCE: There is a dire need for research to identify rational therapies for pancreatic cancer because virtually all patients with this cancer die from disease progression. This year alone, almost 30,000 people in the U.S. will succumb to pancreatic cancer with over 150,000 deaths worldwide. In this grant, we propose studies to identify cellular pathways important in tumor progression in pancreatic cancer with emphasis on novel pathways that could be targeted in therapy.