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国家自然科学基金(81230051)

作品数:13 被引量:48H指数:4
相关作者:张宏权王翔魏潇凡孙小然李雪映更多>>
相关机构:北京大学中国医学科学院北京协和医学院更多>>
发文基金:国家自然科学基金北京市自然科学基金国家重点基础研究发展计划更多>>
相关领域:医药卫生生物学更多>>

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细胞分裂周期相关蛋白7通过增强细胞增殖和干性促进人乳腺癌进程被引量:1
2020年
目的探讨细胞分裂周期相关蛋白7(CDCA7)在人类乳腺癌中的相关功能及潜在的作用机制。方法通过癌症和肿瘤基因图谱(TCGA)数据库分析检索出不同乳腺癌亚型差异表达基因,找到在基底型乳腺癌中高表达基因,在这些基因中找到CDCA7,通过临床患者的相关标本做免疫组织化学分析,确定其研究意义,进而建立CDCA7稳转细胞系,通过集落形成实验、成球实验及流式细胞术分析研究其在乳腺癌中的功能,最后通过Realtime PCR及Western blotting实验分析其在乳腺癌中的分子机制。结果数据库和免疫组织化学结果均显示,CDCA7在基底型乳腺癌细胞中表达高于其他亚型,高表达的CDCA7预示乳腺癌患者不良预后。在luminal细胞系中稳定地过表达CDCA7后,细胞表现出更强的增殖能力,进入分裂期的细胞明显增多,而凋亡细胞显著减少。同时流式细胞术分析表明,过表达CDCA7的细胞表现出了干细胞标记(CD133,乙醛脱氢酶)上调。Real-time PCR和Western blotting结果提示,CDCA7能够上调β-连环蛋白(β-catenin)表达,以此影响Wnt信号通路,并影响细胞增殖和干性。结论 CDCA7作为一个促瘤基因,能够通过依赖β-catenin以及Wnt信号通路的方式来诱导luminal乳腺癌细胞向basal-like亚型转化的能力。
杨得草刘程马集王梦远战军张宏权
关键词:Β-连环蛋白
整合素相关微环境调控肿瘤转移被引量:8
2017年
整合素是肿瘤微环境的重要组成部分,是广泛存在于细胞膜表面的黏附分子,可以识别并结合细胞外基质中相应的配体,参与许多重要的生理过程,包括肿瘤转移.整合素可以促进肿瘤转移的各个阶段,肿瘤微环境也会反过来影响整合素的表达,从而促进癌症的发生发展.
李雪映孙小然张宏权
关键词:整合素肿瘤微环境肿瘤转移
Depletion of Kindlin-2 induces cardiac dysfunction in mice被引量:1
2016年
Kindlin-2, a member of the Kindlin family focal adhesion proteins, plays an important role in cardiac development. It is known that defects in the Z-disc proteins lead to hypertrophic cardiomyopathy(HCM) or dilated cardiomyopathy(DCM). Our previous investigation showed that Kindlin-2 is mainly localized at the Z-disc and depletion of Kindlin-2 disrupts the structure of the Z-Disc. Here, we reported that depletion of Kindlin-2 leads to the disordered myocardial fibers, fractured and vacuolar degeneration in myocardial fibers. Interestingly, depletion of Kindlin-2 in mice induced cardiac myocyte hypertrophy and increased the heart weight. Furthermore, decreased expression of Kindlin-2 led to cardiac dysfunction and also markedly impairs systolic function. Our data indicated that Kindlin-2 not only maintains the cardiac structure but also is required for cardiac function.
Lihua QiYu YuXiaochun ChiDanyu LuYao SongYouyi ZhangHongquan Zhang
关键词:MOUSE
Acetylated HOXB9 at lysine 27 is of differential diagnostic value in patients with pancreatic ductal adenocarcinoma
2020年
Pancreatic ductal adenocarcinoma(PDAC)is the ninth most common human malignancy and the sixth leading cause of cancer-related death in China.AcK27-HOXB9 is a newly identified HOXB9 post-transcriptional modification that can predict the outcome in lung adenocarcinoma and colon cancer well.However,the role of AcK27-HOXB9 in PDAC is unclear.The present study aims to investigate the differential diagnostic role of patients with AcK27-HOXB9 PDAC.Tissue microarrays consisting of 162 pancreatic tumor tissue samples from patients with PDAC and paired normal subjects were used to examine HOXB9 and AcK27-HOXB9 levels and localizations by immunohistochemical analysis and Western blot assay,respectively.HOXB9 was upregulated(P<0.0001),and AcK27-HOXB9(P=0.0023)was downregulated in patients with PDAC.HOXB9 promoted(P=0.0115),while AcK27-HOXB9(P=0.0279)inhibited PDAC progression.AcK27-HOXB9 predicted favorable outcome in patients with PDAC(P=0.0412).AcK27-HOXB9 also suppressed PDAC cell migration in a cell migration assay.The results of this study showed that HOXB9 promoted and AcK27-HOXB9 suppressed PDAC progression.The determination of ratio between HOXB9 and AcK27-HOXB9 exhibited potential diagnostic value in patients with PDAC.
Xiaoran SunJiagui SongJing ZhangJun ZhanWeigang FangHongquan Zhang
Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology被引量:1
2017年
Esophageal cancer (EC) is one of the most lethal malignancies in China, but the etiology and risk factors remain unclear. The integrin-interacting proteins Kindlin-1 and Kindlin-2 are focal adhesion molecules that activate transmembrane receptor integrins and regulate tumor cell growth, invasion, and metastasis. Here, we report that Kindlin-1 and Kindlin-2 are differentially expressed among Chinese EC patients. For this, Kindlin-1 and Kindlin-2 expression was evaluated in 220 EC patients by immunohistochemistry (IHC) and found to be correlated with the EC progression, along with a variety of epidemiologic parameters, including smoking, family EC history, and EC invasion status. Moreover, data downloaded from the Oncomine database revealed that both Kindlin- 1 and Kindlin-2 were upregulated in ECs compared with normal esophageal tissues; although Kindlin-1 was highly expressed in well-differentiated tumors, whereas Kindlin-2 was more prevalent in poorly differentiated tumors. Collectively, these data suggest that Kindlin-1 may inhibit, while Kindlin-2 may promote, EC progression. This study, for the first time, linked the expression of Kindlin-1 and Kindlin-2 with EC family genetic background and living habits, which may help further our understanding of the various causes of EC.
peng wangjun zhanjiagui songyunling wangweigang fangzhihua liuhongquan zhang
关键词:EPIDEMIOLOGY
Kindler syndrome protein Kindlin-1 is mainly expressed in adult tissues originating from ectoderm/endoderm被引量:1
2015年
Mutations of integrin-interacting protein Kindlin-1 cause Kindler syndrome and deregulation of Kindlin-1 is implicated in human cancers. The Kindlin-1-related diseases are confined in limited tissue types. However, Kindlin-1 tissue distribution and the dogma that governs Kindlin-1 expression in normal human body are elusive. This study examined Kindlin-1 expression in normal human adult organs, human and mouse embryonic organs by immunohistochemical analyses. We identified a general principle that the level of Kindlin-1 expression in tissues is tightly correlated with the corresponding germ layers from which these tissues originate. We compared the expression of Kindlin-1 with Kindlin-2 and found that Kindlin-1 is highly expressed in epithelial tissues derived from ectoderm and endoderm, whereas Kindlin-2 is mainly expressed in mesoderm-derived tissues. Likewise, Kindlin-1 was also found highly expressed in endoderm/ectoderm-derived tissues in human and mouse embryos. Our findings indicate that Kindlin-1 may play an importance role in the development of endoderm/ectoderm related tissues.
ZHAN JunYANG MeiZHANG JingGUO YongQingLIU WeiZHANG HongQuan
关键词:ECTODERMENDODERM
Kindlin-1和Kindlin-2的差异表达与食管癌的进程及流行病学特点的相关性被引量:3
2018年
食管癌是中国最致命的恶性肿瘤之一,但其病因和危险因素的分子机制仍不清楚.整合素相互作用蛋白Kindlin-1和Kindlin-2可以激活跨膜受体整合素,调节肿瘤细胞的生长、侵袭和转移.本研究首次发现,在中国食管癌患者中,Kindlin-1和Kindlin-2呈现差异表达的特点.采用免疫组织化学的方法在220例食管癌患者中评估了Kindlin-1和Kindlin-2的表达情况,发现它们不仅与食管癌的进展有关,还与食管癌的各种流行病学因素有关,包括吸烟情况、家族史等.Oncomine数据库也提示,与正常食管组织相比,食管癌中Kindlin-1与Kindlin-2的表达水平都有明显升高.然而,Kindlin-1在分化良好的肿瘤中高度表达,而Kindlin-2则相反,在分化不良的肿瘤中高度表达.另外,Kindlin-1和Kindlin-2在食管癌的进展中分别起到了抑制和促进的作用.此外,本研究首次将Kindlin-1和Kindlin-2的表达水平与食管癌的家族遗传背景和生活习惯联系起来.有助于为食管癌的流行病学特点找到发病分子机制.
王鹏王鹏宋佳桂王允玲方伟岗刘芝华方伟岗
关键词:食管癌流行病学
Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice被引量:6
2019年
Kindlin-2, an integrin-interacting protein, regulates breast cancer progression. However, currently, no animal model to study the role of Kindlin-2 in the carcinogenesis of mammary gland is available. We established a Kindlin-2 transgenic mouse model using a mammary gland-specific promoter, mammary tumor virus(MMTV) long terminal repeat(LTR). Kindlin-2 was overexpressed in the epithelial cells of the transgenic mice. The mammary gland ductal trees were found to grow faster in MMTV-Kindlin-2 transgenic mice than in control mice during puberty. Kindlin-2 promoted mammary gland growth as indicated by more numerous duct branches and larger lumens, and more alveoli were formed in the mammary glands during pregnancy under Kindlin-2 overexpression. Importantly, mammary gland-specific expression of Kindlin-2 induced tumor formation at the age of 55 weeks on average. Additionally, the levels of estrogen receptor and progesterone receptor were decreased, whereas human epidermal growth factor receptor 2 and β-catenin were upregulated in the Kindlin-2-induced mammary tumors. These findings demonstrated that Kindlin-2 induces mammary tumor formation via activation of the Wnt signaling pathway.
Bing LiXiaochun ChiJiagui SongYan TangJuan DuXiaokun HeXiaoran SunZhenwu BiYunling WangJun ZhanHongquan Zhang
关键词:MOUSEMAMMARYGLANDMAMMARYTUMORIGENESISTRANSGENICMOUSE
LATS1 K751 acetylation blocks activation of Hippo signalling and switches LATS1 from a tumor suppressor to an oncoprotein被引量:2
2022年
Large tumor suppressor 1(LATS1)is the key kinase controlling activation of Hippo signalling pathway.Post-translational modifications of LATS1 modulate its kinase activity.However,detailed mechanism underlying LATS1 stability and activation remains elusive.Here we report that LATS1 is acetylated by acetyltransferase CBP at K751 and is deacetylated by deacetylases SIRT3 and SIRT4.Acetylation at K751 stabilized LATS1 by decreasing LATS1 ubiquitination and inhibited LATS1 activation by reducing its phosphorylation.Mechanistically,LATS1 acetylation resulted in inhibition of YAP phosphorylation and degradation,leading to increased YAP nucleus translocation and promoted target gene expression.Functionally,LATS1-K751 Q,the acetylation mimic mutant potentiated lung cancer cell migration,invasion and tumor growth,whereas LATS1-K751 R,the acetylation deficient mutant inhibited these functions.Taken together,we demonstrated a previously unidentified post-translational modification of LATS1 that converts LATS1 from a tumor suppressor to a tumor promoter by suppression of Hippo signalling through acetylation of LATS1.
Siyuan YangWeizhi XuCheng LiuJiaqi JinXueying LiYuhan JiangLei ZhangXianbin MengJun ZhanHongquan Zhang
C1orf106, an innate immunity activator, is amplified in breast cancer and is required for basal-like/luminal progenitor fate decision被引量:2
2019年
Basal-like breast cancer with a luminal progenitor gene expression profile is an aggressive subtype of breast cancer with a poorer prognosis compared with other subtypes.However,genes that specifically promote basal-like breast cancer development remain largely unknown.Here,we report that a novel gene C1orf106 plays an important role in maintaining the feature of basal-like/luminal progenitors.C1orf106 is frequently amplified and overexpressed in basal-like breast cancer and is associated with a poor outcome in patients.In human TCGA database,C1orf106 expression was correlated with upregulation of ELF5 and downregulation of GATA3,two transcription factors that regulate mammary gland stem cell fate.Enhanced expression of C1orf106 promotes tumor progression and expression of basal-like/luminal progenitor marker ELF5;depletion of C1orf106 suppresses tumorigenesis and expression of basal-like/luminal progenitor marker GATA3.These findings suggest that C1orf106 maintains the basal-like/luminal progenitor character through balancing the expression of ELF5 and GATA3.Taken together,we demonstrated that C1orf106 is an important regulator for basal-like/luminal progenitors and targeting C1orf106 is of therapeutic value for breast cancer.
Ji MaCheng LiuDecao YangJiagui SongJing ZhangTianzhuo WangMengyuan WangWeizhi XuXueying LiShigang DingJun ZhanHongquan Zhang
关键词:BASAL-LIKELUMINALPROGENITORGATA3
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