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

描述（由申请人提供）：本提案的研究目的是确定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。尽管DLBCL有可能通过传统的蒽环类药物治疗治愈，但经常观察到反应的变异性，40-50%的患者会复发，并且使用现有的治疗方法无法治愈。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的一个亚群中高表达，ABCG2是参与化疗耐药的转运蛋白ATP结合盒家族的成员，并且ABCG2的表达与GLI1呈正相关。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，并有助于DLBCL的化疗耐药。为了实现这一目标，我们将研究DLBCL中SHH/GLI信号通路失调的致病因素，我们将在体外阐明使用药物抑制剂抑制SHH信号通路的生物学效应，以及沉默SHH信号转导器GLI蛋白的表达，我们将揭示SHH信号通路在化学耐药中的作用。抑制SHH信号对淋巴瘤生长的影响也将在人类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见解，并可能有助于改进目前对该淋巴瘤类型的治疗策略。

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.