Chemoprevention of upper aerodigestive tract cancer by dietary zinc

描述(申请人提供)：虽然自20世纪80年代中期以来，全球癌症死亡率有所下降，但上消化道(UADT)癌，包括食道癌的主要亚型食管鳞癌(ESCC)和舌癌(口腔癌的主要部位)，仍然是致命的。因此，迫切需要阐明致病机制和新的预防策略。据估计，全球膳食缺锌(ZD)影响了30%的人口(分区域为4%-73%)，发展中国家的发病率更高。重要的是，ZD会增加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。利用无偏倚的全基因组表达谱、生物信息学、分子病理学和我们完善的动物模型，我们发现：(I)短期饮食ZD诱导大鼠食道增生相关的促炎介质S100A8和S100A9的过度表达。锌调节S100A8-RAGE相互作用和下游的NF-kB/COX-2信号之间的联系，证据表明锌在早期食道癌的发生中调节炎症途径；(Ii)长时间的ZD诱导癌症相关的炎症基因信号，从而促进ESCC，而口服锌的补充逆转了这一信号，防止了ESCC。(Iii)补锌通过减轻炎症反应，抑制大鼠UADT肿瘤的发展和肿瘤抑制因子缺乏的小鼠品系，证明即使在锌充足的受试者中，锌也具有化学预防作用；(Iv)利用NanStringTM技术，我们发现饮食中的锌以组织特异性的方式改变microRNA的表达。炎症性ZD食管炎具有明显的microRNA基因特征，癌基因miR-31和miR-21过表达，与人ESCC/舌鳞状细胞癌相似。在ZD大鼠中，食道miR-31和miR-21水平与ESCC的发生直接相关。原位杂交研究表明，miR-31和miR-21在大鼠/人舌鳞状细胞癌中的表达上调是细胞类型特异性的，并且对锌治疗有反应。在目标1中，我们验证了饮食ZD在维持炎症过程中绕过了RAGE信号的要求，并通过激活替代炎症途径促进Rage-/-小鼠前胃癌变的假说(S)。在目的2中，我们剖析了膳食锌对致癌大鼠舌癌发生和消退过程中基因表达(microRNA、mRNAs)的调节。在目的3中，我们验证了这样一种假设，即在体内抑制ZD大鼠体内基质中ZD诱导的miR-21可能抵消ZD的促炎作用并抑制ESCC。在目的4中，我们通过研究膳食锌与大鼠食管炎症相关mRNA和microRNA表达变化的剂量反应关系，确定了预防UADT癌对锌的需要量。来自拟议研究的数据应该会促进我们对锌如何在UADT癌症的发生和预防中影响与炎症相关的基因(mRNA和microRNAs)的了解。

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.