Chemoprevention of upper aerodigestive tract cancer by dietary zinc

描述（由申请人提供）：尽管自20世纪80年代中期以来，全球癌症死亡率有所下降，但上呼吸消化道（UADT）癌症，包括食管鳞状细胞癌（ESCC，食管癌的主要亚型）和舌SCC（口腔癌的主要部位），仍然是致命的。因此，迫切需要阐明发病机制和新的预防策略。据估计，全球膳食锌（Zn）缺乏症（ZD）影响30%的人口（各次区域为4-73%），发展中国家的发病率更高。重要的是，ZD增加了UADT癌症的风险。在过去的六年里，我们在了解锌在UADT癌症发展和预防中的分子作用方面取得了重大进展。使用无偏的全基因组表达谱分析、生物信息学、分子病理学和我们充分表征的动物模型，我们发现：（i）大鼠短期饮食ZD诱导与食管增生相关的促炎症介质S100 a8和S100 a9过表达。锌调节S100 A8-ESTA相互作用和下游NF-κ B/考克斯-2信号之间的联系，证据表明，锌调节炎症途径在早期食管癌发生;（ii）延长ZD诱导癌症相关的炎症基因签名，燃料ESCC和口服锌补充逆转这个签名，防止ESCC。(iii)锌补充剂通过减轻炎症来抑制在锌充足饮食的大鼠和肿瘤抑制因子缺陷小鼠品系中的UADT肿瘤发展，这证明即使在锌充足的受试者中，锌也具有化学预防作用;（iv）使用nanoStringTM技术，我们发现饮食ZD以组织特异性方式改变microRNA表达。炎症性ZD食管具有独特的microRNA基因特征，致癌miR-31和miR-21过表达，类似于人ESCC/舌SCC。在ZD大鼠中，食管miR-31和miR-21水平与ESCC的出现直接相关。大鼠/人舌鳞癌中miR-31和miR-21表达的原位杂交研究表明，它们的上调具有细胞类型特异性，并且对锌治疗有反应。在目标1中，我们测试了以下假设：饮食ZD绕过维持炎症对RAGE信号传导的需求，并通过激活替代炎症途径促进Rage-/-小鼠的前胃癌发生。在目标2中，我们剖析了饮食锌调节基因表达（microRNA，mRNA）在舌癌的发展和消退在致癌剂治疗的大鼠。在目的3中，我们检验了由饮食ZD在基质中诱导的ZD大鼠中miR-21的体内抑制可能抵消ZD的促炎作用并抑制ESCC的假设。在目的4中，我们通过研究饮食ZD与大鼠食管中炎症相关mRNA和microRNA表达的改变之间的剂量反应关系，确定预防UADT癌症中对Zn的需求。来自拟议研究的数据应该推进我们对Zn如何影响与UADT癌症的发展和预防中的炎症相关的基因（mRNA和microRNA）的认识。

DESCRIPTION (provided by applicant): Though cancer mortality rates have declined worldwide since the mid 1980s, upper aerodigestive (UADT) cancer, including esophageal squamous cell cancer (ESCC, predominant subtype of esophageal cancer) and tongue SCC (major site of oral cancer), remains deadly. Thus, clarification of pathogenetic mechanisms and new prevention strategies are urgently needed. Global dietary zinc (Zn) deficiency (ZD) is estimated to affect 30% of the population (4-73% across subregions), with higher rates in developing countries. Importantly, ZD increases the risk of UADT cancer. In the past six years we have made significant progress toward understanding the molecular role of Zn in UADT cancer development and prevention. Using unbiased whole genome expression profiling, bioinformatics, molecular pathology, and our well-characterized animal models, we have found that: (i) short-term dietary ZD in rats induces overexpression of proinflammation mediators, S100a8 and S100a9, associated with esophageal hyperplasia. Zn modulates the link between S100A8-RAGE interaction and downstream NF-kB/COX-2 signaling, evidence that Zn regulates an inflammatory pathway in early esophageal carcinogenesis; (ii) prolonged ZD induces a cancer-associated inflammatory gene signature that fuels ESCC and oral Zn replenishment reverses this signature and prevents ESCC. (iii) Zn- supplementation suppresses UADT tumor development in rats and tumor suppressor-deficient mouse strains on a Zn-sufficient diet through attenuation of inflammation, evidence that Zn has chemopreventive effects even in Zn-sufficient subjects; (iv) Using the nanoStringTM technology, we discovered that dietary ZD alters microRNA expression in a tissue-specific manner. The inflammatory ZD esophagus has a distinct microRNA gene signature with overexpression of oncogenic miR-31 and miR-21, resembling that in human ESCC/tongue SCC. In ZD rats esophageal miR-31 and miR-21 levels are directly associated with the appearance of ESCC. In situ hybridization study of miR-31 and miR-21 expression in rat/human tongue SCC reveals that their upregulation is cell type-specific and is Zn-therapy responsive. In Aim 1, we test the hypothesis that dietary ZD bypasses the requirement for RAGE-signaling in sustaining inflammation and promotes forestomach carcinogenesis in Rage-/- mice by activating alternative inflammatory pathway(s). In Aim 2, we dissect dietary Zn modulation of gene expression (microRNA, mRNA) in tongue cancer development and regression in carcinogen-treated rats. In Aim 3, we test the hypothesis that in vivo inhibition of miR-21 in ZD rats that is induced by dietary ZD in stroma might offset the inflammation-promoting effect of ZD and inhibit ESCC. In Aim 4, we determine the requirement for Zn in the prevention of UADT cancer by investigating the dose response relationship between dietary ZD and alterations of inflammation-related mRNA and microRNA expression in the rat esophagus. The data from the proposed studies should advance our knowledge of how Zn affects genes (mRNA and microRNAs) related to inflammation in the development and prevention of UADT cancer.