Role of Sonic Hedgehog Signaling Pathway in Diffuse Large B-Cell Lymphoma

描述(申请人提供)：这项建议的研究目标是确定Sonic Hedgehog(SHH)通路在弥漫性大B细胞淋巴瘤(DLBCL)的生物学、病理学和化疗耐药性中的作用。DLBCL是世界上最常见的淋巴瘤。虽然DLBCL有可能用传统的以蒽环类药物为基础的疗法治愈，但经常观察到反应的多变性，40%-50%的患者会复发，无法用现有的治疗方法治愈。我们的初步数据为SHH/GLI信号通路在DLBCL的发病机制中发挥作用提供了生物学证据。我们还观察到ABCG2在DLBCL中的高表达，并且ABCG2和GLI1的表达呈正相关。ABCG2是参与化疗耐药的转运蛋白家族中的一个成员。基于这些研究，我们假设SHH信号通路的活性升高促进了DLBCL的生长，并参与了DLBCL的化疗耐药。为了达到这一目的，我们将探讨在DLBCL中SHH/GLI信号失控的原因，我们将在体外阐明使用药物抑制剂抑制SHH信号转导蛋白以及沉默SHH信号转导蛋白表达的生物学效应，并揭示SHH信号在化疗耐药中的作用。抑制SHH信号对淋巴瘤生长的影响也将在人DLBCL异种移植模型中进行研究。研究SHH信号在DLBCL中的生物学作用将为DLBCL的发病机制和耐药机制提供新的认识，并可能有助于改进该类型淋巴瘤的治疗策略。 公共卫生相关性：弥漫性大B细胞淋巴瘤(DLBC)是全世界最常见的侵袭性淋巴瘤。了解Sonic Hedgehog(SHH)通路在DLBCL的生物学和化疗耐药性中的作用将为这种淋巴瘤的靶向治疗开辟新的途径。

DESCRIPTION (provided by applicant): The research object of this proposal is to define the role of the Sonic Hedgehog (SHH) pathway in the biology, pathology, and resistance to chemotherapy of diffuse large B-cell lymphomas (DLBCL), the most common lymphoma worldwide. Although DLBCL is potentially curable wit conventional anthracycline-based therapy, variability in response is often observed and 40-50% patients will relapse and will be not cured with the current available therapies. Our preliminary data provide biological evidence that SHH/GLI signaling pathway plays a role in the pathogenesis of DLBCL. We have also observed high expression of ABCG2, a member of ATP binding cassette family of transporter proteins involved in chemoresistance, in a subset of DLBCL and a positive correlation between expression of ABCG2 and GLI1. Based on these studies, we hypothesize that elevated activity of the SHH signaling pathway promotes DLBCL growth and contributes to chemoresistance in DLBCL. To achieve this aim we will investigate causative factors in the deregulation of SHH/GLI signaling in DLBCL, we will elucidate, in vitro, the biological effect of SHH signaling inhibition using pharmacologic inhibitors as well as silencing the expression of the transducers of the SHH signal, the GLI proteins, and we will uncover the contribution of the SHH signaling in chemoresistance. The effects of inhibiting SHH signaling on lymphoma growth will be also studied in a human DLBCL xenograft model. To investigate the biological role of SHH signaling in DLBCL will provide new insights into the pathogenesis and drug resistance mechanisms of DLBCL, and may contribute to improve the current therapeutic strategies in this lymphoma type. PUBLIC HEALTH RELEVANCE: Diffuse large B-cell lymphoma (DLBC) is the most common aggressive lymphoma worldwide. Understanding the role of Sonic Hedgehog (SHH) pathway in the biology and resistance to chemotherapy in DLBCL will open new avenues for targeted therapy in this lymphoma type.