通讯作者：花宝金(1964-),男,黑龙江人,主任医师,博士研究生导师,研究方向: 中医药防治肿瘤复发转移。稿件联系人：蒋树龙,E-mail:jnsljiang@163.com。联系电话：13506383007。

【】　目的：总结JAK2/STAT3/SOCS3信号通路的作用特点及其与肿瘤转移潜能的最新研究进展。方法：应用PubMed及CNKI期刊全文数据库,以“JAK2、STAT3、SOCS3、肿瘤和信号转导”为关键词,检索2000-01~2013-10的相关文献,共检索到英文文献343篇,中文文献66篇。文献纳入标准：１)JAK2/STAT3/SOCS3信号通路的生物学特征及作用机制;２)JAK2/STAT3/SOCS3信号通路与肿瘤微环境的关系及其与肿瘤侵袭转移之间的内在联系。根据纳入标准符合条件的30篇。结果：JAK2/STAT3信号通路的激活参与了肿瘤发生、发展、侵袭和转移等多个环节;SOCS3负性调控JAK2/STAT3通路,从而抑制肿瘤的增殖和生长;STAT3信号通路的激活促成了肿瘤炎性微环境的形成,参与了肿瘤血管生成、上皮间质转化(EMT)、细胞外基质(ECM)降解等多个环节,在肿瘤的侵袭和转移过程中发挥重要作用。结论：JAK2/STAT3/SOCS3信号通路与肿瘤转移密切相关,针对JAK2/STAT3/SOCS3信号通路多靶点干预是肿瘤防治研究的一个新方向。     

Cyy260, a novel small molecule inhibitor,suppresses non-small cell lung cancer cell growth via JAK2/STAT3 pathway

Non-small cell lung cancer (NSCLC) is a malignant tumor that accounts for the most new cancer cases and cancer-related deaths worldwide, and the proliferation and metastasis of NSCLC are the main reasons for treatment failure and patient death. Traditional chemotherapeutic drugs have low selectivity, which can kill cancer cells and cause damage to normal cells at the same time. Therefore, it is particularly important to study therapies that target cancer cells and to find low-toxicity, high-efficiency anticancer drugs. Cyy260 is a novel small molecule inhibitor that we synthesized for the first time. Here, we investigated the in vitro and in vivo antitumor activities of Cyy260 and explored the underlying mechanisms in NSCLC. Cyy260 had a concentration- and time-dependent inhibitory effect on NSCLC cells, but it was less toxic to normal cells. Cyy260 regulated apoptosis through intracellular and extracellular apoptotic pathways. In addition, Cyy260 could also induce cell cycle arrest, thereby inhibiting cell proliferation. Further analysis of molecular mechanisms showed that the JAK2/STAT3 signaling pathway was involved in the antitumor effect mediated by Cyy260. Analysis of subcutaneously transplanted tumors in mice showed that Cyy260 suppressed tumor growth in vivo. Our results proved that Cyy260 is a novel inhibitor of the JAK2/STAT3 pathway thus may have potential in therapy of NSCLC and other cancers.     

Hispidulin suppresses cell growth and metastasis by targeting PIM1 through JAK2/STAT3 signaling in colorectal cancer

Colorectal cancer (CRC) accounts for over 600 000 deaths annually worldwide. The current study aims to evaluate the value of proto‐oncogene PIM1 as a therapeutic target in CRC and investigate the anticancer activity of hispidulin, a naturally occurring phenolic flavonoid compound, against CRC. Immunohistochemistry analysis showed that PIM1 was upregulated in CRC tissue. The role of PIM1 as an oncogene was evidenced by the fact that PIM1 knockdown inhibits cell growth, induces apoptosis, and suppresses invasion. Our results showed that hispidulin exerts antitumor activity in CRC through inhibiting the expression of PIM1. Moreover, our findings revealed that hispidulin downregulated the expression of PIM1 by inhibiting JAK2/STAT3 signaling by generating reactive oxygen species. Furthermore, our in vivo studies showed that hispidulin can significantly inhibit tumor growth and metastasis in CRC. Collectively, our results provide an experimental basis for trialing hispidulin in CRC treatment. PIM1 can be considered a potential therapeutic target in CRC.     

JAK2/STAT3 targeted therapy suppresses tumor invasion via disruption of the EGFRvIII/JAK2/STAT3 axis and associated focal adhesion in EGFRvIII-expressing glioblastoma

Background

As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood.

Methods

Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells.

Results

The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models.

Conclusion

Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.     

Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells

Gastrin, cholecystokinin2 receptor (CCK2R), and cyclooxygenase-2 (COX-2) have been implicated in the carcinogenesis and progression of gastric cancer. Our study demonstrated that antagonist or siRNA against CCK2R blocked amidated gastrin (G17)-induced activation of STAT3 and Akt in gastric cancer cell lines. G17-increased COX-2 expression and cell proliferation were effectively blocked by CCK2R antagonist and inhibitors of JAK2 and PI3K. In addition, knockdown of STAT3 expression significantly attenuated G17-induced PI3K/Akt activation, COX-2 expression, and cell proliferation. These results suggest that CCK2R-mediated COX-2 up-regulation via JAK2/STAT3/PI3K/Akt pathway is involved in the proliferative effect of G17 on human gastric cancer cells.     

Icaritin suppresses multiple myeloma,by inhibiting IL-6/JAK2/STAT3

Icaritin is an active prenylflavonoid derived from Epimedium genus, a traditional Chinese medicine. Icaritin has a wide range of pharmacological and biological activities, including cardiovascular function improvement, hormone regulation and antitumor activity. Here, we investigated the effect of icaritin on multiple myeloma (MM) in vitro and in vivo. Icaritin inhibited cell growth of MM cell line and primary MM cells. In contrast, icaritin had low or no cytotoxic effect on normal hematopoiesis. We also demonstrated that in MM xenograft mouse models, icaritin suppressed tumor growth and decreased serum IL-6 and IgE levels, but did not show adverse reactions such as body weight loss. The anti-MM activity of icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling. We suggest that icaritin can be further tested in clinical trials in MM.     

OPB-31121, a novel small molecular inhibitor,disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells

We investigated the mechanisms of action and antitumor effects of OPB-31121, a novel STAT3 inhibitor, in gastric cancer cells. OPB-31121 downregulated JAK2 and gp130 expression and inhibited JAK2 phosphorylation which leads to inhibition of STAT3 phosphorylation. OPB-31121 inhibited constitutively activated and IL-6-induced JAK/STAT signaling pathway. OPB-31121 decreased cell proliferation in both gastric cancer cells and in a xenograft model, induced the apoptosis of gastric cancer cells, inhibited the expression of antiapoptotic proteins, and showed synergism with 5-fluorouracil and cisplatin. Taken together, our study suggests that STAT3 inhibition with OPB-31121 can be tested in patients with gastric cancer.     

Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell

Tumor angiogenesis is one of the hallmarks of the development in malignant neoplasias and metastasis. Many angiogenesis inhibitors are small molecules from natural products. Indirubin, the active component of a traditional Chinese herbal medicine, Banlangen, has been shown to exhibit antitumor and anti-inflammation effects. But its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is unknown. Here, we identified that indirubin inhibited prostate tumor growth through inhibiting tumor angiogenesis. Using chick chorioallantoic membrane (CAM) assay and mouse corneal model, we found that indirubin inhibited angiogenesis in vivo. We also showed the inhibition activity of indirubin in endothelial cell migration, tube formation and cell survival in vitro. Furthermore, indirubin suppressed vascular endothelial growth factor receptor 2-mediated Janus kinase (JAK)/STAT3 signaling pathway but had little effects on the activity of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase in endothelial cell. Our study provided the first evidence for antitumor angiogenesis activity of indirubin and the related molecular mechanism. Our investigations suggested that indirubin was a potential drug candidate for angiogenesis related diseases.     

Histone deacetylase inhibitor, apicidin, inhibits human ovarian cancer cell migration via class II histone deacetylase 4 silencing

This study examined the molecular mechanisms of apicidin in the modulation of human ovarian cancer SKOV-3 cells invasion and migration. Apicidin markedly decreased histone deacetylase 4 (HDAC4) expression and blocked cell migration and invasion. Cell migration was inhibited via down-regulation of matrix metalloproteinase-2 (MMP-2) and up-regulation of RECK in the HDAC4-blocked SKOV-3 cells. Apicidin significantly suppressed the binding of HDAC4 to Sp1 binding elements of the RECK promoter via repression of HDAC4. In an in vivo model, apicidin suppressed the growth of transplanted SKOV-3 cells by down-regulating HDAC4 and MMP-2. Apicidin may potentially be used as an anti-cancer agent for inhibition of cancer cell migration and invasion through the repression of MMP-2 which is related to the reduction of HDAC4.     

N-Substituted adenosine analogues,a novel class of JAK2 inhibitors,potently block STAT3 signaling in human cancer cells

The JAK2/STAT3 signaling pathway plays a critical role in oncogenesis and malignancy, which makes it a promising anticancer target. We report four N⁶-substituted adenosine analogues (AAs) as potential JAK2/STAT3 inhibitors identified through a STAT3-based high-throughput drug screening system. These AAs exhibited selective anti-cancer activity on human cancer cells and xenograft tumors with constitutively activated STAT3. They rapidly and potently suppressed constitutive and IL-6/IFN-γ-induced JAK2/STAT3 signal activation. In addition, we finally proved that the STAT3 signal blockage by three of these AAs was dependent on specific JAK2 inhibition. These AAs may represent new targeted therapeutic agents for JAK2/STAT3 hyper-activated human cancers.     

隐丹参酮联合顺铂抗非小细胞肺癌NCI-H1975细胞JAK2/STAT3机制研究

目的 探讨隐丹参酮与顺铂联合作用于非小细胞肺癌NCI-H1975细胞具有协同抗肿瘤效应及其可能的分子机制。方法 实验分为对照组、隐丹参酮组、顺铂组及隐丹参酮和顺铂联合用药组(以下简称联合用药组),CCK-8法测定细胞增殖抑制率,流式细胞术测定细胞存活率及凋亡,免疫印迹技术检测用药后凋亡蛋白、抗凋亡分子蛋白表达水平、JAK2/STAT3蛋白及其磷酸化表达水平,激光共聚焦/荧光素酶检测STAT3细胞定位和转录活性。结果 (1)在各时间点,单药组及联合用药组存活率均低于对照组(P＜0.05);与对照组及单药组相比,联合用药组在各时间点均抑制NCI-H1975细胞增殖活性(P＜0.05);(2)联合用药组作用于NCI-H1975细胞24 h后,抗凋亡蛋白Bcl-2、Survivin表达水平下降(P＜0.01),Caspase3和Caspase9活性提高(P＜0.01),p-STAT3及p-JAK2表达水平下降(P＜0.01);(3)联合用药组作用于NCI-H1975细胞后,激光共聚焦检测提示细胞核内STAT3明显减少,核内STAT3活性降低。结论 隐丹参酮联合顺铂作用于非小细胞肺癌NCI-H1975细胞能发挥协同抗肿瘤作用,其机制与抑制信号通路JAK2/STAT3磷酸化表达水平有关。     

MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression

Although dispensable for normal pancreatic function, STAT3 signaling is frequently activated in pancreatic cancers. Consistent downregulation of expression of microRNA let-7 is also characteristic of pancreatic ductal adenocarcinoma (PDAC) biopsy specimens. We demonstrate in this study that re-expression of let-7 in poorly-differentiated PDAC cell lines reduced phosphorylation/activation of STAT3 and its downstream signaling events and reduced the growth and migration of PDAC cells. Let-7 re-expression did not repress expression of STAT3 protein or its activator cytokine interleukin 6 (IL-6). However, let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2. Our study thus identified a mechanism by which STAT3 signaling can be inhibited in pancreatic cancer cells by modifying let-7 expression.