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Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression

机译：通过IMP-3稳定PDPN转录物和功能性串扰形成PDPN表达

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We previously reported that insulin-like growth factor-II mRNA-binding protein-3 (IMP-3) depletion (IMP-3Δ) 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-3Δ 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.
机译：我们先前曾报道胰岛素样生长因子-II mRNA结合蛋白3（IMP-3）耗竭（IMP-3 Δ）被证明可抑制口腔鳞状细胞的侵袭性伪足形成和细胞外基质降解能力细胞癌细胞（OSCC）。在这项研究中，我们发现IMP-3 Δ细胞显着下调了Podoplanin（PDPN）的水平，这导致细胞外基质降解活性的丧失，尽管invadopodia仍在蓬勃发展。使用洋地黄毒苷标记的PDPN 3'UTR识别探针进行RNA原位杂交，并用荧光素酶报道基因下游克隆的PDPN基因的3'UTR进行报告基因检测，我们发现IMP-3耗竭被下调。最有可能通过降低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向邻近基质的局部浸润的原因。两者合计，转化生长因子β1增加PDPN表达，从而通过在低侵袭性OSCC细胞系中增加侵袭伪足形成和细胞外基质降解来增强癌症侵袭。相反，OSCC细胞分泌的白介素-1β刺激了基质成纤维细胞分泌的转化生长因子β1分泌，从而诱导OSCC细胞中PDPN表达。此外，对OSCC患者的回顾性研究发现IMP-3和PDPN表达与OSCC患者的淋巴结转移显着相关。此外，使用免疫组织化学双重染色在原发和淋巴结转移性OSCC细胞中经常检测到IMP-3和PDPN的共表达。因此，IMP-3-PDPN轴可能是抗转移性足病治疗中转移性癌症的敏感靶分子。

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  • 来源
    《Carcinogenesis》 |2012年第11期|p.2135-2146|共12页
  • 作者

    Young Sun Hwang12* Zhang Xianglan13 Kwang-Kyun Park145 and Won-Yoon Chung145*;

  • 作者单位

    1Oral Cancer Research Institute, Yonsei University College of Dentistry, Republic of Korea, 2Department of Dental Hygiene, College of Health Science, Eulji University, Seongnam, Korea, 3Department of Pathology, Yanbian University Hospital, Yanji City, Jilin province, China, 4Department of Oral Biology and 5The Applied Life Sciences, Graduate School, Yonsei University College of Dentistry, Republic of Korea.;

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