Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression
Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression
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DOI：
10.1093/carcin/bgs258
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发表时间：
2012-11-01
期刊：
影响因子：
4.7
通讯作者：
Chung, Won-Yoon
中科院分区：
文献类型：
--
作者：
Hwang, Young Sun;Zhang, Xianglan;Chung, Won-Yoon
我们先前报道胰岛素样生长因子-II mRNA结合蛋白-3(IMP-3)缺失(IMP-3(Delta))可以抑制口腔鳞状细胞癌(OSCC)细胞内膜的形成和细胞外基质的降解能力。在这项研究中，我们发现IMP-3(Delta)细胞显著下调了足阳素(PDPN)的水平，导致细胞外基质降解活性的丧失，尽管内毒素仍在蓬勃发展。用地高辛标记的PDPN的3‘非编码区识别探针进行RNA原位杂交，并与从荧光素酶报告基因下游克隆的PDPN基因的3’非编码区进行报告分析，我们发现IMP-3的缺失被下调，这很可能是通过降低mRNA的稳定性来降低PDPN基因的表达。在异种移植模型中，PDPN耗竭是肿瘤体积减少和局部侵袭到附近间质的原因。综上所述，转化生长因子β1增加了PDPN的表达，这通过增加低侵袭性口腔鳞癌细胞系内膜形成和细胞外基质降解来增强肿瘤的侵袭性。反过来，口腔鳞癌细胞分泌的白介素1β刺激间质成纤维细胞分泌转化生长因子β1，从而诱导口腔鳞癌细胞表达PDPN。此外，对口腔鳞癌患者的回顾性调查发现，IMP-3和PDPN的表达与口腔鳞癌患者的淋巴转移显著相关。免疫组织化学双重染色显示IMP-3和PDPN在原发灶和淋巴结转移灶的口腔鳞癌细胞中均有共同表达。因此，IMP-3-PDPN轴可能是抗侵袭疗法治疗转移性癌症的敏感靶分子。
We previously reported that insulin-like growth factor-II mRNA-binding protein-3 (IMP-3) depletion (IMP-3(Delta)) was shown to inhibit invadopodia formation and extracellular matrix degradation capacity in oral squamous cell carcinoma (OSCC) cells. In this study, we found that IMP-3(Delta) cells significantly downregulated the podoplanin (PDPN) level, which resulted in a loss of extracellular matrix degradation activity, although invadopodia was still thriving. From RNA in situ hybridization using a digoxigenin-labeled 3'UTR recognition probe of PDPN and reporter assay with 3'UTR of the PDPN gene cloned downstream from the luciferase reporter gene, we revealed that IMP-3 depletion was shown to be downregulated, which most probably lowered PDPN gene expression by reducing mRNA stabilization. In a xenograft model, PDPN depletion was the cause of a decrease in tumor volume and regional infiltration into nearby stroma. Taken together, transforming growth factor beta 1 increased PDPN expression, which potentiated cancer invasion through increased invadopodia formation and extracellular matrix degradation in the low invasive OSCC cell line. Reciprocally, interleukin-1 beta secreted by OSCC cells, stimulated transforming growth factor beta 1 secretion from stromal fibroblasts to induce PDPN expression in OSCC cells. In addition, a retrospective investigation of OSCC patients found that IMP-3 and PDPN expression significantly correlated with lymph node metastasis of OSCC patients. Moreover, co-expression of IMP-3 and PDPN were frequently detected both in primary and lymph nodes metastatic OSCC cells using immunohistochemical dual staining. Thus, the IMP-3-PDPN axis may be a sensitive target molecule in anti-invadopodia therapy for the treatment of metastatic cancers.