膜相关胶原 XIII 促进癌症转移并增强失巢凋亡抵抗。
Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance.
机构信息
Department of Laboratory Medicine, The First Hospital of Jilin University, Changchun, 130021, Jilin Province, China.
UK Markey Cancer Center, University of Kentucky, Lexington, KY, 40536, USA.
出版信息
Breast Cancer Res. 2018 Oct 1;20(1):116. doi: 10.1186/s13058-018-1030-y.
BACKGROUND
Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis.
METHODS
We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with β1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student's t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study.
RESULTS
Collagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced β1 integrin activation. Blocking β1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis.
CONCLUSIONS
Our results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance.
背景
在乳腺癌患者中，胶原蛋白表达和沉积的增加与癌症进展和预后不良有关。然而，膜结合胶原在乳腺癌中的功能和调节尚未确定。胶原 XIII 是胶原超家族中的一种 II 型跨膜蛋白。组织培养和基因敲除小鼠模型实验表明，胶原 XIII 参与了某些细胞类型的细胞黏附和分化。在本研究中，我们确定了胶原 XIII 在乳腺癌进展和转移中的作用。
方法
我们利用从人乳腺癌组织中生成的已发表的基因表达谱，分析了胶原 XIII 表达与乳腺癌发生和转移的相关性。利用获得和丧失功能的方法以及 3D 培养测定，我们研究了胶原 XIII 在调节侵袭性肿瘤生长中的作用。利用肿瘤球/类乳腺球体形成测定和细胞脱离培养测定，我们确定了胶原 XIII 是否增强了癌细胞的干性并诱导了抗失巢凋亡。我们还使用β1 整合素功能阻断抗体抑制了胶原 XIII 信号。最后，我们利用肺定植测定和原位乳腺肿瘤模型，研究了胶原 XIII 在调节乳腺癌定植和转移中的作用。本研究采用 Cox 比例风险（对数秩）检验、双侧学生 t 检验（两组）和单向方差分析（三组或更多组）进行分析。
结果
与正常乳腺组织相比，胶原 XIII 在人乳腺癌组织中的表达明显升高。乳腺癌组织中胶原 XIII mRNA 水平的增加与远处无复发生存时间短相关。我们发现胶原 XIII 的表达促进了 3D 培养中的侵袭性肿瘤生长，增强了癌细胞的干性，并诱导了抗失巢凋亡。胶原 XIII 的表达诱导了β1 整合素的激活。阻断β1 整合素的激活显著降低了胶原 XIII 诱导的侵袭和类乳腺球体形成。重要的是，沉默 MDA-MB-231 细胞中的胶原 XIII 降低了肺定植和转移。
结论
我们的结果表明，胶原 XIII 在促进癌症转移、细胞侵袭和抗失巢凋亡方面具有新的功能。
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