TLR4配体和H_2O_2激活的non-Smad信号可增强TGF-β1信号进而促进非侵袭性乳腺癌细胞获得转移潜能
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摘要
目的：多条信号途径的有效激活对促进肿瘤细胞的转移至关重要。TGF-β1具有潜在激活多条与肿瘤转移潜能相关信号途径的能力。然而,非侵袭性肿瘤细胞的转移潜能对TGF-β1的刺激并不敏感。肿瘤微环境中的H202和LPS都具有激活TGF-β1介导的non-Smad途径的潜能,因此,本文旨在探讨H202和LPS能否协同TGF-β1诱导非侵袭性乳腺癌细胞获得转移潜能,同时H2O2和LPS能否促进非侵袭性乳腺癌细胞中TGF-β1信号激活增强。
方法：采用Matrigel侵袭实验和细胞骨架聚集分析来检测肿瘤细胞的侵袭迁移能力；流式细胞术和软琼脂集落形成实验用来检测肿瘤细胞抗失巢凋亡能力；转移和凋亡相关基因的表达水平变化由Real-time RT-PCR和Western blot检测；信号途径的激活水平由Western blot检测；采用免疫组化检测实验性转移模型中肿瘤细胞转移鉴定及增殖情况。
结果：增强的TGF-β1信号能诱导非侵袭性乳腺癌细胞获得转移潜能。单独的TGF-β1不能诱导非侵袭性乳腺癌细胞的Smad和non-Smad途径持续激活。TLR4配体(LPS)和H202协同TGF-β1能有效促进non-Smad信号途径(p38MAPK, ERK, JNK, PI3K和NF-κB)持续激活。激活的MAPK和PI3K信号又可通过下调Nm23-H1,上调TβRⅠ和TβRⅡ的表达对TGF-β1信号激活产生一个正反馈调控,从而进一步激活多条信号途径。同时,激活增强的TGF-β1信号也可诱导SNAI2表达进一步上调,后者又能促进TPRⅡ表达。因此,经TGF-β1/H2O2/LPS长时间诱导后,Smad和non-Smad信号持续激活逐渐增强。与信号途径激活模式一致,经TGF-β1/H2O2/LPS长时间诱导后,乳腺癌细胞的侵袭迁移和抗失巢凋亡能力也逐渐增强。重要的是,裸鼠实验转移模型结果表明,TGF-β1/H2O2/LPS诱导的转移潜能足以促进非侵袭性的乳腺癌细胞从血管中外渗并且在肺内形成转移病灶。
结论：H2O2/LPS可激活增强非侵袭性乳腺癌细胞中TGF-β1信号,诱导Smad和non-Smad信号持续激活增强,从而诱导非侵袭性乳腺癌细胞获得转移潜能。转移是导致肿瘤患者死亡最主要的原因。信号的激活增强可诱导肿瘤细胞获得更高的转移潜能,因此,靶向阻断某一个刺激因素或某一条信号途径的激活可能成为肿瘤综合治疗策略之一。
Aim:The efficient activation of multiple signaling pathways is the important driving force for tumor cell metastasis. TGF-β1has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-β1was inefficient in inducing metastatic potential of many non-invasive human tumor cells. It has been found that TLR4ligand and H2O2also have the potential to activate non-Smad pathways which could be activated by TGF-β1. Therefore, in this study we investigated whether TGF-β1could induce the metastatic potential of non-invasive tumor cells in presence of TLR4ligand and/or H2O2, and whether TLR4ligand and/or H2O2could enhance TGF-β1signaling in non-invasive tumor cells.
Methods:Invasive capacity was evaluated using matrigel invasion assay and actin polymerization analysis. Anoikis-resistance was determined by flow cytometry and colony formation in soft-agar. The expression of genes was detected using real-time RT-PCR and Western blot. The activation of signaling pathways was detected by Western blot. The metastasis and proliferation of tumor cell in experimental mouse metastasis model were analyzed by immunohistochemistry.
Results:Here we report that the enhancement of TGF-β1signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-β1alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4ligand (LPS) and H2O2cooperated with TGF-β1to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-β1signaling by down-regulating Nm23-H1expression and up-regulating the expression of TβRⅠ and TβRⅡ, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-β1signaling induced higher expression of SNAI2, which also promoted TβRⅡ expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. The metastatic potential induced by TGF-β1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice.
Conclusion:The findings in this study demonstrated that H2O2/LPS could enhance TGF-β1signaling to induce the sustained activation of both Smad and non-Smad pathways in non-invasive breast cancer cells, and thus promoting the metastatic capability of non-invasive breast cancer cells. Metastases are responsible for most cancer deaths. Given that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, targeting one of these stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.
方法：采用Matrigel侵袭实验和细胞骨架聚集分析来检测肿瘤细胞的侵袭迁移能力；流式细胞术和软琼脂集落形成实验用来检测肿瘤细胞抗失巢凋亡能力；转移和凋亡相关基因的表达水平变化由Real-time RT-PCR和Western blot检测；信号途径的激活水平由Western blot检测；采用免疫组化检测实验性转移模型中肿瘤细胞转移鉴定及增殖情况。
结果：增强的TGF-β1信号能诱导非侵袭性乳腺癌细胞获得转移潜能。单独的TGF-β1不能诱导非侵袭性乳腺癌细胞的Smad和non-Smad途径持续激活。TLR4配体(LPS)和H202协同TGF-β1能有效促进non-Smad信号途径(p38MAPK, ERK, JNK, PI3K和NF-κB)持续激活。激活的MAPK和PI3K信号又可通过下调Nm23-H1,上调TβRⅠ和TβRⅡ的表达对TGF-β1信号激活产生一个正反馈调控,从而进一步激活多条信号途径。同时,激活增强的TGF-β1信号也可诱导SNAI2表达进一步上调,后者又能促进TPRⅡ表达。因此,经TGF-β1/H2O2/LPS长时间诱导后,Smad和non-Smad信号持续激活逐渐增强。与信号途径激活模式一致,经TGF-β1/H2O2/LPS长时间诱导后,乳腺癌细胞的侵袭迁移和抗失巢凋亡能力也逐渐增强。重要的是,裸鼠实验转移模型结果表明,TGF-β1/H2O2/LPS诱导的转移潜能足以促进非侵袭性的乳腺癌细胞从血管中外渗并且在肺内形成转移病灶。
结论：H2O2/LPS可激活增强非侵袭性乳腺癌细胞中TGF-β1信号,诱导Smad和non-Smad信号持续激活增强,从而诱导非侵袭性乳腺癌细胞获得转移潜能。转移是导致肿瘤患者死亡最主要的原因。信号的激活增强可诱导肿瘤细胞获得更高的转移潜能,因此,靶向阻断某一个刺激因素或某一条信号途径的激活可能成为肿瘤综合治疗策略之一。
Aim:The efficient activation of multiple signaling pathways is the important driving force for tumor cell metastasis. TGF-β1has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-β1was inefficient in inducing metastatic potential of many non-invasive human tumor cells. It has been found that TLR4ligand and H2O2also have the potential to activate non-Smad pathways which could be activated by TGF-β1. Therefore, in this study we investigated whether TGF-β1could induce the metastatic potential of non-invasive tumor cells in presence of TLR4ligand and/or H2O2, and whether TLR4ligand and/or H2O2could enhance TGF-β1signaling in non-invasive tumor cells.
Methods:Invasive capacity was evaluated using matrigel invasion assay and actin polymerization analysis. Anoikis-resistance was determined by flow cytometry and colony formation in soft-agar. The expression of genes was detected using real-time RT-PCR and Western blot. The activation of signaling pathways was detected by Western blot. The metastasis and proliferation of tumor cell in experimental mouse metastasis model were analyzed by immunohistochemistry.
Results:Here we report that the enhancement of TGF-β1signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-β1alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4ligand (LPS) and H2O2cooperated with TGF-β1to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-β1signaling by down-regulating Nm23-H1expression and up-regulating the expression of TβRⅠ and TβRⅡ, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-β1signaling induced higher expression of SNAI2, which also promoted TβRⅡ expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-β1/H2O2/LPS. The metastatic potential induced by TGF-β1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice.
Conclusion:The findings in this study demonstrated that H2O2/LPS could enhance TGF-β1signaling to induce the sustained activation of both Smad and non-Smad pathways in non-invasive breast cancer cells, and thus promoting the metastatic capability of non-invasive breast cancer cells. Metastases are responsible for most cancer deaths. Given that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, targeting one of these stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.
引文
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1. Gallego MI, Bierie B, Hennighausen L. Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways. Oncogene,2003,22(52): 8498-8508.
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4. Brown KA, Aakre ME, Gorska AE, et al. Induction by transforming growth factor-beta1 of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 2004,6(3):R215-231.
5. Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009,19(2):156-172.
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1. Parvani JG, Taylor MA, Schiemann WP. Noncanonical TGF-beta signaling during mammary tumorigenesis. J Mammary Gland Biol Neoplasia,2011,16(2): 127-146.
2. Brown KA, Aakre ME, Gorska AE, et al. Induction by transforming growth factor-betal of epithelial to mesenchymal transition is a rare event in vitro. Breast Cancer Res 2004,6(3):R215-231.
3. Liu SL, Lin X, Shi DY, et al. Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways. Arch Biochem Biophys,2002,406(2):173-182.
4. Okoh V, Deoraj A, Roy D. Estrogen-induced reactive oxygen species-mediated signalings contribute to breast cancer. Biochim Biophys Acta,2011,1815(1): 115-133.
5. Yoon SO, Park SJ, Yoon SY, et al. Sustained production of H2O2 activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. J Biol Chem,2002 277:30(33),271-30282.
6. Diya Z, Lili C, Shenglai L, et al. Lipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-lbeta, TNF-alpha and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS. Innate Immun,2008,14(2): 99-107.
7. Fortin CF, Cloutier A, Ear T, et al. A class IA PI3K controls inflammatory cytokine production in human neutrophils. Eur J Immunol,2011,41(6): 1709-1719.
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