High Mobility Group A1 Chromatin Regulators in Colon Carcinogenesis

摘要 背景：我们拟阐明高迁移率族A1介导的分子机制 （HMGA 1）染色质重塑蛋白在结直肠癌发生过程中的作用。HMGA 1基因是一种高度 在胚胎发育过程中表达，但在大多数成体组织中出生后沉默。HMGA 1也是 在多种分化差的癌症中过度表达，高水平预示着不良结果。HMGA1 蛋白质通过“打开”染色质并将转录复合物募集到DNA来调节基因表达。 虽然很明显，染色质调节因子有助于控制核结构和细胞命运的决定， 对潜在的机制知之甚少。在这里，我们专注于HMGA 1在结直肠癌（CRC）。 我们认为HMGA 1促进CRC肿瘤进展的科学前提是基于以下初步假设： 结果：1）与非恶性结肠上皮相比，HMGA 1在CRC中高度过表达，2） 沉默HMGA 1阻断致癌特性，防止转移进展，并消除癌干细胞 3）在转基因小鼠中，Hmga 1过表达：a）诱导过度增殖， 小肠和大肠中的异常隐窝形成和癌前息肉病，和，B）扩张小肠 肠干细胞（ISC）池（Xian等，Nature Comm; 2017），5）令人惊讶的是， Hmga 1还通过诱导Sox 9产生潘氏细胞来帮助“建立”干细胞生态位，潘氏细胞支持并 培养小ISCs，6）HMGA 1和SOX 9在人结肠上皮中呈正相关， 在结肠癌中显著上调，和，7）炎症信号和致癌原细菌 与临床前肿瘤模型中Hmga 1表达相关。 总而言之，这些有趣的结果支持了以下假设：1）Hmga 1是正常所需的 结肠上皮中干细胞功能和组织稳态，2）失调的HMGA 1破坏了这一点 平衡，并通过染色质结构的异常变化驱动癌发生和肿瘤进展 3）炎症信号和特定的促癌细菌诱导HMGA 1驱动HMGA 1表达， 4）识别与HMGA 1过表达相关的机制将揭示新的途径 可以调节来治疗甚至预防结肠癌的发生。 目的/方法：为了验证这一点，我们提出了以下具体目的：1）定义致癌细胞和干细胞 结肠上皮中依赖于HMGA 1的表型，2）为了阐明表观遗传改变和遗传学改变， HMGA 1在致癌过程中发挥作用的途径，以及，3）为了确定是否靶向 在临床前模型中，hmga 1可有效减轻或预防结肠癌的发生。 影响：我们希望阐明诱导HMGA 1以及下游途径的机制， 在CRC中的HMGA 1。这项工作可以揭示结肠癌发病机制的新模式，并导致 治疗甚至预防这种可怕癌症的新方法。

ABSTRACT Background: We propose to elucidate molecular mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin remodeling proteins during colorectal carcinogenesis. The HMGA1 gene is highly expressed during embryogenesis, but silenced postnatally in most adult tissues. HMGA1 is also overexpressed in diverse, poorly differentiated cancers and high levels portend adverse outcomes. HMGA1 proteins modulate gene expression by “opening” chromatin and recruiting transcriptional complexes to DNA. While it is clear that chromatin regulators help to govern nuclear architecture and cell fate decisions, the underlying mechanisms are poorly understood. Here, we focus on HMGA1 in colorectal cancer (CRC). Our scientific premise that HMGA1 fosters tumor progression in CRC is based on the following preliminary results: 1) HMGA1 is highly overexpressed in CRC compared to non-malignant colonic epithelium, 2) Silencing HMGA1 blocks oncogenic properties, prevents metastatic progression, and depletes cancer stem cells in preclinical CRC models, 3) In transgenic mice, Hmga1 overexpression: a) induces hyperproliferation, aberrant crypt formation, and premalignant polyposis in small and large intestines, and, b) expands the small intestinal stem cell (ISC) pool by amplifying Wnt signals (Xian et al, Nature Comm; 2017), 5) Surprisingly, Hmga1 also helps to “build” a stem cell niche by inducing Sox9 to generate Paneth cells, which support and nurture small ISCs, 6) HMGA1 and SOX9 are positively correlated in human colon epithelium and both become markedly up-regulated in colon cancer, and, 7) Inflammatory signals and procarcinogenic bacteria associate with Hmga1 expression in preclinical tumor models. Together, these intriguing results support the following hypotheses: 1) Hmga1 is required for normal stem cell function and tissue homeostasis in colonic epithelium, 2) Deregulated HMGA1 disrupts this equilibrium and drives carcinogenesis and tumor progression through aberrant changes in chromatin structure and gene expression, 3) Inflammatory signals and specific pro-carcinogenic bacteria induce HMGA1 to drive tumor progession, and, 4) Identifying mechanisms linked to HMGA1 overexpression will reveal novel pathways that could be modulated to treat, or even prevent, colon carcinogenesis. Aims/Approach: To test this, we propose the following Specific Aims: 1) To define oncogenic and stem cell phenotypes dependent upon HMGA1 in colonic epithelium, 2) To elucidate epigenetic alterations and genetic pathways through which HMGA1 functions during carcinogenesis, and, 3) To determine whether targeting Hmga1 is effective in mitigating or preventing colon carcinogenesis in preclinical models. Impact: We expect to elucidate mechanisms that induce HMGA1 as well as downstream pathways governed by HMGA1 in CRC. This work could reveal a new paradigm for colon cancer pathogenesis and lead to novel approaches to treat, or even prevent, this formidable cancer.