KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages
KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages
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DOI：
10.1042/cs20201259
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发表时间：
2021-02-01
期刊：
影响因子：
6
通讯作者：
Xiu, Dian-rong
中科院分区：
文献类型：
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作者：
Li, Mu-xing;Wang, Hang-yan;Xiu, Dian-rong
肿瘤微环境（TME）在胰腺导管腺癌（PDAC）的发生发展中起着关键作用。然而，调节PDAC细胞和TME之间的串扰的因素在很大程度上是未知的。在本研究中，我们鉴定了一种长非编码RNA（lncRNA）KLHDC 7 B趋异转录本（KLHDC 7 B-DT），该转录本在PDAC中上调，并与PDAC患者的生存率低相关。功能测定表明KLHDC 7 B-DT增强PDAC细胞增殖、迁移和侵袭。机制上，发现KLHDC 7 B-DT直接结合IL-6启动子，诱导IL-6启动子区域的开放染色质结构，激活IL-6转录，并上调IL-6表达和分泌。PDAC组织中KLHDC 7 B-DT的表达与IL-6的表达呈正相关。KLHDC 7 B-DT通过诱导PDAC细胞分泌IL-6，以自分泌方式激活STAT 3信号通路。此外，KLHDC 7 B-DT还以旁分泌方式激活巨噬细胞中的STAT 3信号，从而诱导巨噬细胞M2极化。KLHDC 7 B-DT过表达的PDAC细胞致敏的巨噬细胞促进PDAC细胞增殖、迁移和侵袭。阻断IL-6/STAT 3信号转导逆转了KLHDC 7 B-DT对巨噬细胞M2极化和PDAC细胞增殖、迁移和侵袭的影响。总之，KLHDC 7 B-DT通过IL-6诱导的巨噬细胞M2极化和IL-6激活的PDAC细胞中的STAT 3信号传导增强PDAC细胞的恶性行为。KLHDC 7 B-DT诱导的PDAC细胞和巨噬细胞之间的串扰是PDAC的潜在治疗靶点。
Tumor microenvironment (TME) exerts key roles in pancreatic ductal adenocarcinoma (PDAC) development. However, the factors regulating the cross-talk between PDAC cells and TME are largely unknown. In the present study, we identified a long noncoding RNA (lncRNA) KLHDC7B divergent transcript (KLHDC7B-DT), which was up-regulated in PDAC and correlated with poor survival of PDAC patients. Functional assays demonstrated that KLHDC7B-DT enhanced PDAC cell proliferation, migration, and invasion. Mechanistically, KLHDC7B-DT was found to directly bind IL-6 promoter, induce open chromatin structure at IL-6 promoter region, activate IL-6 transcription, and up-regulate IL-6 expression and secretion. The expression of KLHDC7B-DT was positively correlated with IL-6 in PDAC tissues. Via inducing IL-6 secretion, KLHDC7B-DT activated STAT3 signaling in PDAC cells in an autocrine manner. Furthermore, KLHDC7B-DT also activated STAT3 signaling in macrophages in a paracrine manner, which induced macrophage M2 polarization. KLHDC7B-DT overexpressed PDAC cells-primed macrophages promoted PDAC cell proliferation, migration, and invasion. Blocking IL-6/STAT3 signaling reversed the effects of KLHDC7B-DT on macrophage M2 polarization and PDAC cell proliferation, migration, and invasion. In conclusion, KLHDC7B-DT enhanced malignant behaviors of PDAC cells via IL-6-induced macrophage M2 polarization and IL-6-activated STAT3 signaling in PDAC cells. The cross-talk between PDAC cells and macrophages induced by KLHDC7B-DT represents potential therapeutic target for PDAC.