Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong higher Education Institutes, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
J Cell Mol Med. 2018 Jan;22(1):655-667. doi: 10.1111/jcmm.13351. Epub 2017 Oct 5.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Long non-coding RNAs (lncRNAs) are important regulators in pathological processes, yet their potential roles in PDAC are poorly understood. Here, we identify a fundamental role for a novel lincRNA, linc00511, in the progression of PDAC. Linc00511 levels in PDAC tissue specimens and cell lines were examined by quantitative real-time PCR. Corresponding adjacent non-neoplastic tissues were used as controls. The function of linc00511 in PDAC cell lines was determined by RNA interference approach in vitro and in vivo. Fluorescence in situ hybridization (FISH) was used to characterize linc00511 expression in PDAC cells. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were obtained from bioinformatic analysis, luciferase assays and RIP assays. The association between the linc00511/hsa-miR29b-3p axis and VEGFA was verified by Western blotting assay. Immunohistochemistry was performed to evaluate the expression of VEGFA in PDAC samples. The aberrant up-regulation of linc00511 was detected in PDAC cell lines and patient specimens compared with controls. An increase in linc00511 expression indicates the adverse clinical pathological characteristics and poor prognosis. Functionally, linc00511 depletion in PDAC cells decreased proliferation, migration, invasion and endothelial tube formation. Mechanistically, linc00511 could up-regulate VEGFA via its competing endogenous RNA (ceRNA) activity on hsa-miR-29b-3p. In summary, our results define an important axis controlling proliferation, invasion and tumour angiogenesis in PDAC. Linc00511 is a novel lncRNA that plays a significant regulatory role in the pathogenesis and progression of PDAC. Thus, Linc00511 represents a new prognostic biomarker to predict clinical outcome of PDAC patients after surgery and may serve as a potential therapeutic target for PDAC treatment.
胰腺导管腺癌(PDAC)是一种致命的恶性肿瘤。长链非编码 RNA(lncRNA)是病理过程中的重要调节剂,但它们在 PDAC 中的潜在作用仍知之甚少。在这里,我们确定了一种新型 lincRNA linc00511 在 PDAC 进展中的基本作用。通过定量实时 PCR 检查 PDAC 组织标本和细胞系中的 linc00511 水平。相应的相邻非肿瘤组织用作对照。通过 RNA 干扰方法在体外和体内确定 linc00511 在 PDAC 细胞系中的功能。荧光原位杂交(FISH)用于表征 PDAC 细胞中的 linc00511 表达。通过生物信息学分析、荧光素酶测定和 RIP 测定获得竞争性内源性 RNA(ceRNA)机制的见解。通过 Western blot 测定验证 linc00511/hsa-miR29b-3p 轴与 VEGFA 之间的关联。免疫组织化学用于评估 PDAC 样本中 VEGFA 的表达。与对照相比,在 PDAC 细胞系和患者标本中检测到 linc00511 的异常上调。linc00511 表达增加表明临床病理特征不良和预后不良。功能上,PDAC 细胞中 linc00511 的耗竭降低了增殖、迁移、侵袭和内皮管形成。从机制上讲,linc00511 可以通过其对 hsa-miR-29b-3p 的竞争性内源 RNA(ceRNA)活性上调 VEGFA。总之,我们的结果定义了一个控制 PDAC 增殖、侵袭和肿瘤血管生成的重要轴。Linc00511 是一种新型 lncRNA,在 PDAC 的发病机制和进展中发挥重要调节作用。因此,Linc00511 是预测 PDAC 患者手术后临床结局的新预后生物标志物,可能成为 PDAC 治疗的潜在治疗靶点。