Bao Bin, Ali Shadan, Ahmad Aamir, Li Yiwei, Banerjee Sanjeev, Kong Dejuan, Aboukameel Amro, Mohammad Ramzi, Van Buren Eric, Azmi Asfar S, Sarkar Fazlul H
1 Department of Pathology, Karmanos Cancer Institute, Wayne State University , Detroit, Michigan.
Stem Cells Dev. 2014 Aug 15;23(16):1947-58. doi: 10.1089/scd.2013.0551. Epub 2014 Jun 6.
Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer-stem-like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLC characteristics and functions. Here we show that isolated CD44(+)/CD133(+)/EpCAM(+) cells (triple-marker-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells, display aggressive characteristics, such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with overexpression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs, including let-7, miR-30, miR-125b, and miR-335, in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-marker-positive cells), consistent with the downregulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLC characteristics, and may serve as novel targets for therapy.
胰腺癌（PC）是最致命的癌症之一。其较高的死亡率部分归因于治疗抗性和转移的早期发生。癌症干细胞样细胞（CSLCs）的存在已被广泛认为是PC肿瘤侵袭性的原因。新出现的证据表明，CSLCs具有增强的细胞生长、细胞迁移/侵袭、转移和治疗抗性能力，这导致临床结果不佳。然而，CSLCs在肿瘤发生和进展中的分子作用尚不清楚。因此，对CSLCs的机制理解和靶向杀伤可能为PC的治疗提供一种新的治疗策略。人们已经普遍认为，微小RNA（miRNAs）通过对多个基因的失调在肿瘤发生和进展过程中发挥关键作用。此外，miRNAs的失调表达也可能在CSLCs的特征和功能调节中起关键作用。在这里，我们表明，从人PC细胞系MiaPaCa-2和L3.6pl细胞中分离出的CD44(+)/CD133(+)/EpCAM(+)细胞（三标记阳性细胞）表现出侵袭性特征，如细胞生长增加、克隆形成能力、细胞迁移和自我更新能力，这与CSLC特征/标志物的过表达一致。我们还发现CSLCs中有400多种miRNAs表达失调，包括let-7、miR-30、miR-125b和miR-335。作为概念验证，miR-125b的敲低导致CSLCs（三标记阳性细胞）的肿瘤细胞侵袭性受到抑制，这与CD44、EpCAM、EZH2和蜗牛的下调一致。这些结果清楚地表明了miRNAs在调节CSLC特征中的重要性，并可能作为新的治疗靶点。
