Zhang Yanqing, Zhang Xin, Zhang Yi, Xu Han, Wei Zichen, Wang Xin, Li Yan, Guo Junrong, Wu Fan, Fang Xiao, Pang Lei, Deng Bin, Yu Duonan
Institute of Translational Medicine, Yangzhou University Medical College, Yangzhou, China.
Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou University Medical College, 136 Jiangyang Road, Yangzhou, Jiangsu Province, 225009, China.
Ann Hematol. 2023 Dec;102(12):3499-3513. doi: 10.1007/s00277-023-05434-9. Epub 2023 Sep 15.
Myc is a pivotal protooncogenic transcription factor that contributes to the development of almost all Burkitt's lymphomas and about one-third of diffuse large B-cell lymphomas. How B-cells sustain their uncontrolled proliferation due to high Myc is not yet well defined. Here, we found that Myc trans-represses the expression of murine LAPTM5, a gene coding a lysosome-associated protein, by binding to two E-boxes in the LAPTM5 promoter. While the product of intact mRNA (CDS+3'UTR) of LAPTM5 failed to suppress the growth of B-lymphomas, either the protein coded by coding sequence (CDS) itself or the non-coding 3'-untranslated region (3'UTR) mRNA was able to inhibit the growth of B-lymphomas. Moreover, Myc trans-activated miR-17-3p, which promoted tumor growth. Strikingly, LAPTM5 3'UTR contains 11 miR-17-3p-binding sites through which the LAPTM5 protein synthesis was inhibited. The functional interplay between low LAPTM5 mRNA and high miR-17-3p due to high Myc in B-lymphomas leads to further dampening of tumor-suppressive LAPTM5 protein, which promotes tumor progression. Our results indicate that Myc inhibits LAPTM5 expression in B-lymphoma cells by transcriptional and post-transcriptional modifications.
Myc是一种关键的原癌基因转录因子，几乎参与了所有伯基特淋巴瘤以及约三分之一的弥漫性大B细胞淋巴瘤的发生发展。B细胞如何因Myc水平升高而维持其不受控制的增殖，目前尚不清楚。在此，我们发现Myc通过与LAPTM5启动子中的两个E盒结合，反式抑制小鼠LAPTM5（一种编码溶酶体相关蛋白的基因）的表达。虽然LAPTM5完整mRNA（编码区+3'非翻译区）的产物未能抑制B淋巴瘤的生长，但编码序列（CDS）本身编码的蛋白质或非编码3'非翻译区（3'UTR）mRNA都能够抑制B淋巴瘤的生长。此外，Myc反式激活促进肿瘤生长的miR-17-3p。引人注目的是，LAPTM5 3'UTR包含11个miR-17-3p结合位点，通过这些位点LAPTM5蛋白质合成受到抑制。B淋巴瘤中由于Myc水平升高导致的低LAPTM5 mRNA与高miR-17-3p之间的功能相互作用，导致肿瘤抑制性LAPTM5蛋白进一步减少，从而促进肿瘤进展。我们的结果表明，Myc通过转录和转录后修饰抑制B淋巴瘤细胞中LAPTM5的表达。
