LncRNA HOTTIP modulates cancer stem cell properties in human pancreatic cancer by regulating HOXA9

• Published in: Cancer letters Vol. 410; pp. 68 - 81
• Main Authors: Fu, Zhiqiang, Chen, Changhao, Zhou, Quanbo, Wang, Yinxue, Zhao, Yue, Zhao, Xiaohui, Li, Wenzhu, Zheng, Shangyou, Ye, Huilin, Wang, Lin, He, Zhanghai, Lin, Qing, Li, Zhihua, Chen, Rufu
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.12.2017; Elsevier Limited
• Subjects: Animals; Cancer stem cells; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - surgery; CD44 antigen; Cell Line, Tumor; Disease-Free Survival; Drug resistance; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; HOTTIP; HOXA9; Humans; Long noncoding RNAs; Medical research; Mesenchyme; Mice, Inbred BALB C; Mice, Nude; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Non-coding RNA; Oct-4 protein; Pancreatectomy; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - surgery; Phenotype; Protein Binding; Proteins; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Rodents; Stem cells; Studies; Time Factors; Tumorigenesis; Tumors; Wnt; Wnt protein; Wnt Signaling Pathway; β-Catenin; United States > US; HOXA9; HOTTIP; Wnt; Cancer stem cells; Pancreatic ductal adenocarcinoma; Long noncoding RNAs
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.09.019

Our previous study demonstrated that long non-coding RNA (lncRNA) HOTTIP was maximally expressed in PDAC, and promoted cancer cell progression and epithelial to mesenchymal transition (EMT). Numerous studies indicated that lncRNAs or EMT supported cancer stem cells. However, the role of HOTTIP in pancreatic cancer stem cells (PCSCs) remains unclear. Here, we evaluated the role and mechanism of HOTTIP in PCSCs. First, we analyzed the relationship between HOTTIP expression and overall or disease-free survival in 90 patients with PDAC after radical resection. Patients with higher HOTTIP expression had shorter disease-free survival and overall survival than those with lower expression. Expression of HOTTIP and other lncRNAs was detected in PCSCs and non-PCSCs by laser capture microdissection (LCM). HOTTIP was highly expressed in PCSCs. In addition, in vitro assays showed that HOTTIP alterations affected stemness, including sphericity, tumorigenesis, and stem factors (LIN28, NANOG, OCT4, and SOX2) and markers (ALDH1, CD44, and CD133). Mechanistically, HOTTIP mediated HOXA9 to enhance the Wnt/β-catenin pathway by binding to WDR5 in PCSCs. In vivo results showed that HOTTIP or HOXA9 alterations influenced stemness. Our results indicate that the HOTTIP/WDR5/HOXA9/Wnt axis contributes to PCSC stemness and is a potential therapeutic target for PDAC. •HOTTIP is critical for maintaining PCSCs properties.•HOTTIP mediates HOXA9 expression by directly binding WDR5 in PCSCs.•HOTTIP/WDR5/HOXA9 axis enhances PCSCs properties by promoting Wnt/β-catenin signal pathway.