The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer.
The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer.
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长非编码 RNA HOTTIP 通过调节 HOXA13 促进胰腺癌进展和吉西他滨耐药
DOI：
10.1186/s12967-015-0442-z
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发表时间：
2015-03-12
影响因子：
7.4
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Li Z;Zhao X;Zhou Y;Liu Y;Zhou Q;Ye H;Wang Y;Zeng J;Song Y;Gao W;Zheng S;Zhuang B;Chen H;Li W;Li H;Li H;Fu Z;Chen R
人类基因组编码许多长的非编码RNA（lncRNA）。然而，它们的生物学功能、分子机制以及与胰腺导管腺癌（PDAC）相关的预后价值仍有待阐明。在这里，我们确定了lncRNA HOXA转录在远端（HOTTIP）的PDAC的进展和耐药性的基本作用。采用高通量芯片技术检测8例PDAC组织和4例胰腺组织中lncRNA和mRNA的表达谱。使用定量实时PCR来确定PDAC细胞系和来自患者的90个PDAC样品中HOTTIP和HOXA 13转录物的水平。HPDE 6细胞（永生化的人胰腺导管上皮细胞）和相应的邻近非肿瘤组织分别用作对照。通过体外靶向敲低HOTTIP和HOXA 13来评估HOTTIP和HOXA 13在细胞增殖、侵袭和上皮-间质转化中的功能。CCK-8测定、集落形成测定和裸鼠中的异种移植物用于研究HOTTIP的靶向沉默是否可以使胰腺癌细胞对吉西他滨敏感。进行免疫组织化学以研究HOXA 13表达与患者结局之间的关系。微阵列分析显示，HOTTIP是PDAC组织中与胰腺组织相比最显著上调的lncRNA之一。定量PCR进一步证实，与对照相比，HOTTIP水平在PDAC细胞系和患者样品中增加。在功能上，HOTTIP沉默通过改变细胞周期进程导致增殖停滞，并通过抑制胰腺癌中的上皮-间充质转化而损害细胞侵袭。此外，HOTTIP的抑制增强了吉西他滨在体外和体内的抗肿瘤作用。此外，通过RNA干扰敲低HOXA 13（siHOXA 13）揭示HOTTIP促进PDAC细胞增殖、侵袭和化学抗性，至少部分地通过调节HOXA 13。免疫组化结果显示HOXA 13高表达与PDAC患者的淋巴结转移、组织分化差和总生存率降低相关。HOTTIP作为一种重要的肿瘤促进剂，通过调节HOXA 13促进细胞增殖、侵袭和化疗耐药性。因此，HOTTIP/HOXA 13轴是PDAC潜在的治疗靶点和分子生物标志物。本文的在线版本（doi：10.1186/s12967-015-0442-z）包含补充材料，可供授权用户使用。
The human genome encodes many long non-coding RNAs (lncRNAs). However, their biological functions, molecular mechanisms, and the prognostic value associated with pancreatic ductal adenocarcinoma (PDAC) remain to be elucidated. Here, we identify a fundamental role for the lncRNA HOXA transcript at the distal tip (HOTTIP) in the progression and chemoresistance of PDAC. High-throughput microarrays were performed to detect the expression profiles of lncRNAs and messenger RNAs in eight human PDAC tissues and four pancreatic tissues. Quantitative real-time PCR was used to determine the levels of HOTTIP and HOXA13 transcripts in PDAC cell lines and 90 PDAC samples from patients. HPDE6 cells (immortalized human pancreatic ductal epithelial cells) and corresponding adjacent non-neoplastic tissues were used as controls, respectively. The functions of HOTTIP and HOXA13 in cell proliferation, invasion, and epithelial-mesenchymal transition were evaluated by targeted knockdown in vitro. CCK-8 assays, colony formation assays, and xenografts in nude mice were used to investigate whether targeted silencing of HOTTIP could sensitize pancreatic cancer cells to gemcitabine. Immunohistochemistry was performed to investigate the relationship between HOXA13 expression and patient outcome. Microarray analyses revealed that HOTTIP was one of the most significantly upregulated lncRNAs in PDAC tissues compared with pancreatic tissues. Quantitative PCR further verified that HOTTIP levels were increased in PDAC cell lines and patient samples compared with controls. Functionally, HOTTIP silencing resulted in proliferation arrest by altering cell-cycle progression, and impaired cell invasion by inhibiting epithelial-mesenchymal transition in pancreatic cancer. Additionally, inhibition of HOTTIP potentiated the antitumor effects of gemcitabine in vitro and in vivo. Furthermore, knockdown of HOXA13 by RNA interference (siHOXA13) revealed that HOTTIP promoted PDAC cell proliferation, invasion, and chemoresistance, at least partly through regulating HOXA13. Immunohistochemistry results revealed that higher HOXA13 expression was correlated with lymph node metastasis, poor histological differentiation, and decreased overall survival in PDAC patients. As a crucial tumor promoter, HOTTIP promotes cell proliferation, invasion, and chemoresistance by modulating HOXA13. Therefore, the HOTTIP/HOXA13 axis is a potential therapeutic target and molecular biomarker for PDAC. The online version of this article (doi:10.1186/s12967-015-0442-z) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
37.3
作者：
Gibb EA;Brown CJ;Lam WL
通讯作者：
Lam WL
影响因子：
37.3
作者：
Korc, M
通讯作者：
Korc, M
影响因子：
9.8
作者：
Chang HY;Sneddon JB;Alizadeh AA;Sood R;West RB;Montgomery K;Chi JT;van de Rijn M;Botstein D;Brown PO
通讯作者：
Brown PO
影响因子：
0.6
作者：
Mohamadkhani A
通讯作者：
Mohamadkhani A