Department of Human Anatomy, Sapienza University of Rome, Rome, Italy.
Biomed Pharmacother. 2013 Feb;67(1):7-16. doi: 10.1016/j.biopha.2012.08.003. Epub 2012 Sep 16.
Hypoxia-inducible factor-1α (HIF-1α) is frequently overexpressed and activated in many cancer types. However, its regulation and function in thyroid carcinomas are only partially known. Aim of our study was to demonstrate that adaptation to the hypoxic micro-environment by human papillary thyroid carcinoma (PTC) cells, in the absence of leukocyte infiltrate, induces a "molecular inflammation" process characterized by the expression of a large set of genes normally involved in inflammation. To address this, tumor, peritumor or normal host tissue from eleven human PTC surgical samples, were separated by laser capture microdissection (LCMD) and studied by real-time quantitative PCR and Western blot. In such condition, we observed an increased expression and activation of HIF-1α, NF-kB and pro-inflammatory genes only in tumor tissues. Importantly, an anti-inflammatory gene such as SOCS-1 was markedly down-regulated in tumor tissue compared to surrounding normal host tissue. Similar results were found in fine-needle aspiration biopsy (FNAB)-derived specimens from PTC and in hypoxic human papillary thyroid tumor cell line, BCPAP. Moreover, we also detected an elevated expression of metalloproteinase-9 (MMP9) both in solid tumor and in hypoxic-treated BCPAP cells. Our findings reveal that, in human PTC tumor, hypoxic conditions are accompanied by up-regulation of pro-inflammatory genes, down-regulation of anti-inflammatory genes and increased expression of MMP9. We propose that a better understanding of the pro- and anti-inflammatory pathways involved in the "molecular inflammation" process even in the absence of leukocyte, may help to clarify progression toward malignancy and may prove useful for new anti-tumor strategy.
缺氧诱导因子-1α（HIF-1α）在许多癌症类型中经常过度表达和激活。然而，其在甲状腺癌中的调节和功能仅部分已知。我们的研究目的是证明在没有白细胞浸润的情况下，人类甲状腺乳头状癌（PTC）细胞适应缺氧微环境会诱导“分子炎症”过程，其特征是表达大量通常参与炎症的基因。为了解决这个问题，通过激光捕获显微切割（LCMD）分离了来自 11 个人类 PTC 手术样本的肿瘤、肿瘤周围或正常宿主组织，并通过实时定量 PCR 和 Western blot 进行研究。在这种情况下，我们仅在肿瘤组织中观察到 HIF-1α、NF-kB 和促炎基因的表达和激活增加。重要的是，与周围正常宿主组织相比，肿瘤组织中抗炎基因如 SOCS-1 明显下调。在 PTC 的细针抽吸活检（FNAB）衍生标本和缺氧人甲状腺乳头状癌细胞系 BCPAP 中也发现了类似的结果。此外，我们还在实体瘤和缺氧处理的 BCPAP 细胞中检测到金属蛋白酶-9（MMP9）的表达升高。我们的研究结果表明，在人 PTC 肿瘤中，缺氧条件伴随着促炎基因的上调、抗炎基因的下调和 MMP9 的表达增加。我们提出，更好地理解“分子炎症”过程中涉及的促炎和抗炎途径，即使在没有白细胞的情况下，也可能有助于阐明向恶性肿瘤的进展，并可能对新的抗肿瘤策略有用。
