Richardson Douglas S, Gujral Taranjit S, Peng Susan, Asa Sylvia L, Mulligan Lois M
Department of Pathology and Molecular Medicine, Division of Cancer Biology and Genetics, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Cancer Res. 2009 Jun 1;69(11):4861-9. doi: 10.1158/0008-5472.CAN-08-4425.
Mutations to the RET proto-oncogene occur in as many as one in three cases of thyroid cancer and have been detected in both the medullary (MTC) and the papillary (PTC) forms of the disease. Of the nearly 400 chromosomal rearrangements resulting in oncogenic fusion proteins that have been identified to date, the rearrangements that give rise to RET fusion oncogenes in PTC remain the paradigm for chimeric oncoprotein involvement in solid tumors. RET-associated PTC tumors are phenotypically indolent and relatively less aggressive than RET-related MTCs. The mechanism(s) contributing to the differences in oncogenicity of RET-related MTC and PTC remains unexplained. Here, through cellular and molecular characterization of the two most common RET/PTC rearrangements (PTC1 and PTC3), we show that RET/PTC oncoproteins are highly oncogenic when overexpressed, with the ability to increase cell proliferation and transformation. Further, RET/PTCs activate similar downstream signaling cascades to wild-type RET, although at different levels, and are relatively more stable as they avoid lysosomal degradation. Absolute quantitation of transcript levels of RET, CCDC6, and NCOA4 (the 5' fusion genes involved in PTC1 and PTC3, respectively) suggest that these rearrangements result in lower RET expression in PTCs relative to MTCs. Together, our findings suggest PTC1 and PTC3 are highly oncogenic proteins when overexpressed, but result in indolent disease compared with RET-related MTCs due to their relatively low expression from the NCOA4 and CCDC6 promoters in vivo.
RET原癌基因的突变在多达三分之一的甲状腺癌病例中出现，并且在甲状腺髓样癌（MTC）和甲状腺乳头状癌（PTC）这两种疾病形式中均已被检测到。在迄今已鉴定出的近400种导致致癌融合蛋白的染色体重排中，PTC中产生RET融合癌基因的重排仍然是嵌合癌蛋白参与实体瘤的范例。与RET相关的PTC肿瘤在表型上生长缓慢，并且相比于与RET相关的MTC侵袭性相对较小。导致RET相关的MTC和PTC致癌性差异的机制仍未得到解释。在这里，通过对两种最常见的RET/PTC重排（PTC1和PTC3）进行细胞和分子特征分析，我们发现RET/PTC癌蛋白在过表达时具有高度致癌性，能够增加细胞增殖和转化。此外，RET/PTC激活与野生型RET相似的下游信号级联反应，尽管程度不同，并且由于它们避免了溶酶体降解而相对更稳定。对RET、CCDC6和NCOA4（分别参与PTC1和PTC3的5'融合基因）转录水平的绝对定量表明，相对于MTC，这些重排在PTC中导致RET表达较低。总之，我们的研究结果表明，PTC1和PTC3在过表达时是高度致癌的蛋白质，但由于它们在体内从NCOA4和CCDC6启动子的表达相对较低，与RET相关的MTC相比导致疾病生长缓慢。
