Veite-Schmahl Michelle J, Joesten William C, Kennedy Michael A
Department of Chemistry and Biochemistry, Miami University, 651 E. High St., Oxford, OH 45056, USA.
Br J Cancer. 2017 Aug 22;117(5):639-647. doi: 10.1038/bjc.2017.216. Epub 2017 Jul 11.
Pancreatic cancer is currently the third leading cause of cancer deaths in the United States and it is predicted to become the second by the year 2030. High-mobility group A1 protein (HMGA1) is an oncogenic transcription factor, localised and active in cell nuclei, that is linked to tumour progression in many human cancers, including pancreatic cancer. Overexpression of HMGA1 renders cancer cells resistant to chemotherapy. Although the Ptf1a-Cre; LSL-KrasG12D transgenic mouse is perhaps the most widely utilised animal model for human pancreatic cancer, expression levels of HMGA1 in pancreata from this mouse model have not been characterised.
Quantitative immunohistochemical analysis was used to determine nuclear HMGA1 levels in pancreatic tissue sections from Ptf1a-Cre; LSL-KrasG12D mice aged 5, 11, and 15 months. The H Score method was used for quantitative analysis.
The HMGA1 levels were significantly elevated in pancreatic intraepithelial neoplasia (PanIN) epithelia compared with untransformed acinar tissues or fibroinflammatory stroma.
The PanINs have long been regarded as precancerous precursors to pancreatic adenocarcinoma. Significantly elevated HMGA1 levels observed in the nuclei of PanINs in Ptf1a-Cre; LSL-KrasG12D mice validate this animal model for investigating the role that HMGA1 plays in cancer progression and testing therapeutic approaches targeting HMGA1 in human cancers.
胰腺癌目前是美国癌症死亡的第三大主要原因，预计到2030年将成为第二大原因。高迁移率族蛋白A1（HMGA1）是一种致癌转录因子，定位于细胞核并在其中发挥作用，与包括胰腺癌在内的许多人类癌症的肿瘤进展有关。HMGA1的过表达使癌细胞对化疗产生抗性。尽管Ptf1a-Cre; LSL-KrasG12D转基因小鼠可能是用于人类胰腺癌研究的最广泛使用的动物模型，但尚未对该小鼠模型胰腺中HMGA1的表达水平进行表征。
采用定量免疫组织化学分析方法，测定5、11和15月龄的Ptf1a-Cre; LSL-KrasG12D小鼠胰腺组织切片中核HMGA1水平。采用H评分法进行定量分析。
与未转化的腺泡组织或纤维炎性基质相比，胰腺上皮内瘤变（PanIN）上皮中的HMGA1水平显著升高。
长期以来，PanIN一直被视为胰腺腺癌的癌前病变。在Ptf1a-Cre; LSL-KrasG12D小鼠的PanIN细胞核中观察到的HMGA1水平显著升高，验证了该动物模型可用于研究HMGA1在癌症进展中的作用以及测试针对人类癌症中HMGA1的治疗方法。
