Hasegawa S, Eguchi H, Nagano H, Konno M, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Nishida N, Koseki J, Nishimura T, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H
1] Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan [2] Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
Br J Cancer. 2014 Oct 14;111(8):1572-80. doi: 10.1038/bjc.2014.454. Epub 2014 Aug 12.
Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumour recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterise the clinical significance.
We established gemcitabine-resistant Panc1 cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumourigenicity. The expression was studied in 24 pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining.
The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR-1246 expression via CCNG2. In vivo, we found that miR-1246 could increase tumour-initiating potential and induced drug resistance. A high expression level of miR-1246 was correlated with a worse prognosis and CCNG2 expression was significantly lower in those patients.
miR-1246 expression was associated with chemoresistance and CSC-like properties via CCNG2, and could predict worse prognosis in pancreatic cancer patients.
胰腺癌预后较差,因其对化疗高度耐药且易复发,这些特性被认为与癌症干细胞(CSCs)有关。微小RNA(miRNA)调控与CSCs相关的癌症进展的各种分子机制。本研究旨在鉴定候选miRNA并阐明其临床意义。
我们建立了吉西他滨耐药的Panc1细胞,并通过成球培养诱导其具有CSC样特性。通过微阵列分析筛选候选miRNA。通过评估体外细胞生长和体内致瘤性进行过表达和敲低实验。在激光捕获显微切割后的24例胰腺癌样本中以及通过免疫组织化学染色研究其表达。
胰腺癌细胞的体外药物敏感性根据miR-1246通过CCNG2的表达而改变。在体内,我们发现miR-1246可增加肿瘤起始潜能并诱导耐药性。miR-1246的高表达水平与较差的预后相关,且这些患者中CCNG2的表达显著降低。
miR-1246的表达通过CCNG2与化疗耐药和CSC样特性相关,并可预测胰腺癌患者的较差预后。