microRNA-193a stimulates pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings.
microRNA-193a stimulates pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings.
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microRNA-193a 通过调节 TGF-β2/TGF-βRIII 信号刺激胰腺癌细胞增殖和转移
DOI：
10.1186/s13046-018-0697-3
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发表时间：
2018-02-13
期刊：
影响因子：
--
通讯作者：
Tian L
中科院分区：
文献类型：
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作者：
Fang C;Dai CY;Mei Z;Jiang MJ;Gu DN;Huang Q;Tian L
背景胰腺癌具有复发率高、预后差的特点。在临床实践中，放射治疗被广泛用于胰腺癌治疗。然而，由于肿瘤再增殖以及放射后的复发和转移，结果仍然不理想。因此，研究其分子机制并制定相应的治疗策略是非常必要的。我们以前的研究表明，死于放化疗的细胞可以刺激存活的胰腺癌细胞的再增殖。然而，我们仍然对死亡细胞如何引起胰腺癌细胞再增殖知之甚少。本研究旨在探讨TGF-β2在胰腺癌放疗后的变化及其对microRNA-193 a（miR-193 a）表达的调节作用，并探讨其在胰腺癌放疗后再增殖和转移中的作用。分别采用Western blot、real-time PCR和双荧光素酶报告基因检测方法，从分子水平、细胞水平和实验动物模型水平检测miR-193 a和TGF-β2/TGF-βRIII信号通路。采用流式细胞仪分析、创伤愈合和transwell实验、血管内皮细胞穿透实验、生物发光成像等方法评价胰腺癌不同治疗方法后的生物学行为。结果miR-193 a在受照胰腺癌死亡细胞中高表达，相应地提高存活细胞中miR-193 a的表达水平，进一步促进胰腺癌在体内外的再增殖和转移。miR-193 a通过抑制TGF-β2/TGF-βRIII/SMADs/E2 F6/c-Myc信号通路，加速胰腺癌细胞周期，促进细胞增殖和再增殖，甚至通过抑制TGF-β2/TGF-βRIII/ARHGEF 15/ABL 2通路，破坏正常细胞间连接，促进转移。发现胰腺癌细胞中miR-193 a的敲低或TGF-β2/TGF-βRIII信号传导的恢复可阻断放射后胰腺癌的再增殖和转移。在PDX模型中，miR-193 a拮抗剂联合放射治疗可显著抑制胰腺癌细胞的再增殖和转移，进一步提高放射治疗后的生存率。结论miR-193 a通过调节TGF-β2/TGF-βRIII信号通路促进胰腺癌细胞的再增殖和转移，miR-193 a可能是胰腺癌再增殖和转移的潜在治疗靶点。
BackgroundPancreatic cancer characterizes high recurrence and poor prognosis. In clinical practice, radiotherapy is widely used for pancreatic cancer treatment. However, the outcome remains undesirable due to tumor repopulation and following recurrence and metastasis after radiation. So, it is highly needed to explore the underlying molecular mechanisms and accordingly develop therapeutic strategies. Our previous studies revealed that dying cells from chemoradiation could stimulate repopulation of surviving pancreatic cancer cells. However, we still knew little how dying cells provoke pancreatic cancer cell repopulation. We herein would explore the significance of TGF-β2 changes and investigate the modulation of microRNA-193a (miR-193a), and identify their contributions to pancreatic cancer repopulation and metastasis.MethodsIn vitro and in vivo repopulation models were established to mimic the biological processes of pancreatic cancer after radiation. Western blot, real-time PCR and dual-luciferase reporter assays were accordingly used to detect miR-193a and TGF-β2/TGF-βRIII signalings at the level of molecular, cellular and experimental animal model, respectively. Flow cytometry analysis, wound healing and transwell assay, vascular endothelial cell penetration experiment, and bioluminescence imaging were employed to assessthe biological behaviors of pancreatic cancer after different treatments. Patient-derived tumor xenograft (PDX) mice models were established to evaluate the therapeutic potential of miR-193a antagonist on pancreatic cancer repopulation and metastasis after radiation.ResultsmiR-193a was highly expressed in the irradiated pancreatic cancer dying cells, accordingly elevated the level of miR-193a in surviving cells, and further promoted pancreatic cancer repopulation and metastasis in vitro and in vivo. miR-193a accelerated pancreatic cancer cell cycle and stimulated cell proliferation and repopulation through inhibiting TGF-β2/TGF-βRIII/SMADs/E2F6/c-Myc signaling, and even destroyed normal intercellular junctions and promoted metastasis via repressing TGF-β2/TGF-βRIII/ARHGEF15/ABL2 pathway. Knockdown of miR-193a or restoration of TGF-β2/TGF-βRIII signaling in pancreatic cancer cells was found to block pancreatic cancer repopulation and metastasis after radiation. In PDX models, the treatment in combination with miR-193a antagonist and radiation was found to dramatically inhibit pancreatic cancer cell repopulation and metastasis, and further improved the survival after radiation.ConclusionsOur findings demonstrated that miR-193a stimulated pancreatic cancer cell repopulation and metastasis through modulating TGF-β2/TGF-βRIII signalings, and miR-193a might be a potential therapeutic target for pancreatic cancer repopulation and metastasis.
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影响因子：
29.4
作者：
FRIESS, H;YAMANAKA, Y;KORC, M
通讯作者：
KORC, M
垂死的神经胶质瘤细胞通过 caspase 3 依赖性机制建立促血管生成微环境
影响因子：
9.7
作者：
Feng X;Yu Y;He S;Cheng J;Gong Y;Zhang Z;Yang X;Xu B;Liu X;Li CY;Tian L;Huang Q
通讯作者：
Huang Q
影响因子：
4.8
作者：
Ahmed, MM;Alcock, A;Freeman, JW
通讯作者：
Freeman, JW
影响因子：
5.4
作者：
Conacci-Sorrell, Maralice;McFerrin, Lisa;Eisenman, Robert N.
通讯作者：
Eisenman, Robert N.
Caspase 3 介导的癌症放射治疗过程中肿瘤细胞增殖的刺激。
影响因子：
82.9
作者：
通讯作者：
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