Crk介导的信号途径对肿瘤淋巴道转移调控及其用于肿瘤诊治的探讨

批准号:
81272186
项目类别:
面上项目
资助金额:
70.0 万元
负责人:
刘淑清
依托单位:
学科分类:
H1801.肿瘤病因
结题年份:
2016
批准年份:
2012
项目状态:
已结题
项目参与者:
王冬梅、殷玉玲、张军、郭春梅、祝文君、石际、李妲
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中文摘要
恶性肿瘤早期淋巴道转移发生机制不清,一直是肿瘤学研究难题。原癌基因表达产物接头蛋白Crk参与整合蛋白等分子信号转导,正成为肿瘤转移恶化研究的热点分子,但其与肿瘤淋巴道转移的关系尚未涉及。本组前期工作发现1)Crk及其下游分子Rack1在高淋巴道转移力鼠肝癌细胞株Hca-F中表达均明显上调,且CRKI上调与肺鳞癌发展和胃癌淋巴道转移呈正相关;2)抑制整合蛋白信号强度能降低肝癌荷瘤鼠的肿瘤转移和死亡率,明显降低Hca-F迁移侵袭能力。本项目拟1)通过调控Crk在肝癌高低淋巴道转移力Hca-F和Hca-P细胞中的蛋白表达水平,考察该变化对肿瘤细胞体内外黏附、侵袭、迁移及淋巴道转移潜能的影响;2)研究整合蛋白/Crk信号转导通路中关键蛋白分子及CrkII/CrkL自抑制磷酸化水平的相互关系,明确其分子调控机制;3)探讨CRK作为临床肿瘤转移预警潜在靶标的可行性,为恶性肿瘤诊治提供新的可行性途径。
英文摘要
The mechanism of early lymphatic metastasis for malignant tumors is unclear, which is still the leading problem for oncology. As the expression product of proto-oncogene, the adaptor protein Crk is involved in signal transduction pathways such as integrin signaling transduction. The Crk family proteins are becoming hotspot molecules for tumor metastasis and maligancy, however, the association of Crk with tumor lymphatic metastasis has not been touched. Previous study from our group indicated that 1) Crk and its down-stream signal molecule Rack1 were both up-regulated signifcantly in mouse hepatocarcinoma cell (Hca-F) with high lymphatic metastatic potential. The up-regulation of CRKI was found to be positively correlated with the development of lung squamous cell carcinoma and lymphatic metastasis of gastric cancer; 2)The suppression of integrin siganl could decrease tumor metastasis and mortality rate of mice with hepatocarcinoma and could significantly decrease the mobility ability of Hca-F. This proposal aims to 1) regulate the expression levels of Crk family members in tumor cells with high (Hca-F) and low (Hca-P) lymphatic metastasis potentials and to investigate the corresponding changes on the capacities of tumor cell adhesion, invasion, motility and metastasis in vitro and/or in vivo; 2) to unreveal the associations and regulation mechanism among the critical proteins and autoinhibitory phosphorylation of CrkII/CrkL involved in the integrin-Crk signal transduction pathway; 3) to investigate the possibibity of CRK utilized as potential predictive markers for clinical tumor metastasis and provide a new feasible approach to the diagnosis and treatment of malignant tumors.
恶性肿瘤的淋巴道转移发生机制不清。Crk家族参与细胞多种生理活动,与淋巴道转移关系尚不明确。本组前期结果表明Crk在淋巴道转移力不同鼠肝癌Hca-F和Hca-P细胞株中差异表达显著。本课题研究表明:1)CrkI过表达促进Hca-P增殖、黏附、迁移、侵袭及生存活力,促进小鼠足垫成瘤和淋巴结转移能力;CrkI下调则Hca-P过度死亡;2)CrkⅡ过表达促进Hca-P增殖、克隆形成、迁移及侵袭能力;CrkⅡ下调抑制Hca-P增殖、克隆形成、迁移及侵袭能力、淋巴结黏附能力;CrkⅡ对p130cas/Crk/Dock180/Rac1信号通路影响很小;3)CrkL蛋白主要分布于Hca-P 细胞质中;过表达抑制Hca-P增殖、克隆形成、迁移及侵袭能力;下调能够促进Hca-P增殖、迁移和侵袭能力,促进小鼠足垫成瘤及体内淋巴结转移;4)在CML细胞株中,CrkL下调抑制K562增殖、克隆形成、迁移和侵袭、促进细胞凋亡、降低 Imatinib mesylate 耐药性,将细胞周期阻滞在S 期,并促进细胞向巨核细胞分化;CrkL通过调控多条信号转 导 通 路 包 括 PI3K-Akt/mTOR 、 MAPK 、 FAK/Src 、 CrkL-STAT5 和p130CAS/CrkL/Dock180/RAC1 来抑制K562细胞的恶性转化;CrkL下调增强Raf/MEK/ERK通路分子及Elk-1表达水平,促进细胞的红系分化; CrkL和CrkⅡ在K562细胞中存在相互作用,下调CrkL可代偿性的增加CrkII表达;5)rAdinbitor抑制Hca-P增殖并促其凋亡、抑制体外黏附、迁移和侵袭能力;其通过CrkI介导的Crk/DOCK180/ Rac、MEK/ERK和PI3K/Akt/mTOR通路来调控增殖、黏附、迁移和侵袭能力;抑制H22和Hca-F增殖,降低其侵袭和迁移能力;抑制肿瘤血管新生、生长和转移,降低肿瘤恶化程度,延长荷瘤小鼠生存周期;6)CrkI/II及CrkL蛋白水平在肝癌组织中高表达;CrkL蛋白在肾癌组织样本中高表达,而CrkI和CrkII表达差异不显著;CrkL mRNA水平在血癌CML及ALL样本中高表达,CML缓解后表达水平趋于正常;而CrkI/II在血癌样本中表达差异不显著。Crk家族通过介导的信号通路,在不同类型的肿瘤中特异性发挥作用,是恶性肿瘤潜在的靶分子。
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科研奖励列表
会议论文列表
专利列表
CRKL overexpression suppresses in vitro proliferation, invasion and migration of murine hepatocarcinoma Hca-P cells
CRKL过表达抑制小鼠肝癌Hca-P细胞的体外增殖、侵袭和迁移
DOI:10.1016/j.biopha.2014.10.025
发表时间:2015-02-01
期刊:BIOMEDICINE & PHARMACOTHERAPY
影响因子:7.5
作者:Lin, Qiuyue;Sun, Ming-Zhong;Liu, Shuqing
通讯作者:Liu, Shuqing
DOI:--
发表时间:2014
期刊:Future Oncology
影响因子:3.3
作者:Chunmei Guo;Shuqing Liu;Ming-Zhong Sun;
通讯作者:
DOI:10.1016/j.biochi.2015.06.026
发表时间:2015-09
期刊:Biochimie
影响因子:3.9
作者:Ming-Zhong Sun;Yanhua Cui;Chunmei Guo;Baochang Zhao;Shuqing Liu
通讯作者:Ming-Zhong Sun;Yanhua Cui;Chunmei Guo;Baochang Zhao;Shuqing Liu
ANXA5 level is linked to in vitro and in vivo tumor malignancy and lymphatic metastasis of murine hepatocarcinoma cell
ANXA5水平与小鼠肝癌细胞的体外和体内肿瘤恶性肿瘤和淋巴转移有关
DOI:10.2217/fon.15.289
发表时间:2016-01-01
期刊:FUTURE ONCOLOGY
影响因子:3.3
作者:Peng, Boya;Liu, Shuqing;Sun, Ming-Zhong
通讯作者:Sun, Ming-Zhong
DOI:--
发表时间:2012
期刊:国际病理科学与临床杂志
影响因子:--
作者:毕建华;崔艳花;孙明忠;刘淑清
通讯作者:刘淑清
遗传性耳聋小鼠内耳毛细胞缺失的分子机制研究
- 批准号:81100722
- 项目类别:青年科学基金项目
- 资助金额:22.0万元
- 批准年份:2011
- 负责人:刘淑清
- 依托单位:
国内基金
海外基金
