Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p.
Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p.
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外泌体来源的 lnc-HOXB8-1:2 通过海绵 hsa-miR-6825-5p 诱导肿瘤相关巨噬细胞浸润，促进神经内分泌分化型结直肠癌进展
DOI：
10.1186/s12885-022-09926-1
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发表时间：
2022-08-27
期刊：
影响因子：
3.8
通讯作者：
中科院分区：
文献类型：
--
作者：
结直肠癌（CRC）细胞中的神经内分泌分化（NED）已被发现数十年，我们之前的荟萃分析表明，具有神经内分泌分化的CRC患者的5年生存率较低。近年来，越来越多的研究发现外泌体来源的长链非编码RNA（lncRNA）在肿瘤的发生、发展和转移中起重要作用。然而，外泌体来源的lncRNA在伴有神经内分泌分化的结直肠癌中的功能和机制尚不完全清楚。在一项105例患者的回顾性研究中评估了NED的临床意义。通过下一代测序和生物信息学分析，选择lnc-HOXB 8 -1：2进行进一步研究。采用免疫组织化学、qRT-PCR、western blot、transwell试验、免疫荧光试验、荧光原位杂交试验和双荧光素酶报告基因试验，确定外泌体来源的lnc-HOXB 8 -1：2在结直肠癌伴NED中的致癌作用。还探索了lnc-HOXB 8 -1：2/hsa-miR-6825- 5 p/CXCR 3轴的潜在机制。NED是结直肠癌进展和死亡的危险因素。lnc-HOXB 8 -1：2来源于神经内分泌分化的结肠癌细胞分泌的外泌体。M2巨噬细胞的比例以及肿瘤相关巨噬细胞（TAM）的迁移和侵袭能力在添加神经内分泌分化的CRC细胞来源的外泌体后显著增加。更令人兴奋的是，在TAM中lnc-HOXB 8 -1：2的表达和CXCR 3的蛋白水平也上调。通过米兰达软件预测了lnc-HOXB 8 -1：2/hsa-miR-6825- 5 p/CXCR 3轴，并通过双荧光素酶报告基因测定得到证实。此外，lnc-HOXB 8 -1：2表达的增加伴随着hsa-miR-6825- 5 p表达的下调和CXCR 3蛋白水平的上调。hsa-miR-6825- 5 p的过表达也降低了CXCR 3的表达。来源于神经内分泌分化的CRC细胞的外泌体中的lnc-HOXB 8 -1：2充当竞争性结合hsa-miR-6825- 5 p的ceRNA以上调CXCR 3表达并导致TAM浸润和M2极化，这促进神经内分泌分化的CRC进展。在线版本包含补充材料，可通过10.1186/s12885-022-09926-1获得。
Neuroendocrine differentiation (NED) in colorectal cancer (CRC) cells has been known for decades, and our previous meta-analysis indicated that CRC patients with neuroendocrine differentiation have a lower 5-year survival rate. In recent years, an increasing number of studies have found that exosome-derived long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. However, the functions and mechanism of exosome-derived lncRNAs in CRC with neuroendocrine differentiation are not yet fully clear. The clinical significance of NED was assessed in a retrospective study of 105 patients. Next-generation sequencing and bioinformatics analysis were conducted to select lnc-HOXB8-1:2 for further study. Using immunohistochemistry, qRT–PCR, western blot, transwell assay, immunofluorescence assay, fluorescence in situ hybridization assay and dual-luciferase reporter assay, the oncogenic role of exosome-derived lnc-HOXB8-1:2 was determined in CRC with NED. The mechanism underlying the lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was also explored. NED was a risk factor for the progression and mortality of CRC. lnc-HOXB8-1:2, derived from exosomes secreted by neuroendocrine differentiated colon cancer cells, was identified in our study. The proportion of M2 macrophages and the migration and invasion capacities of tumor-associated macrophages (TAMs) markedly increased after the addition of neuroendocrine differentiated CRC cell-derived exosomes. More excitingly, the expression of lnc-HOXB8-1:2 and the protein level of CXCR3 were also upregulated in TAMs. The lnc-HOXB8-1:2/hsa-miR-6825-5p/CXCR3 axis was predicted via miRanda software and confirmed by the dual-luciferase reporter assay. Furthermore, the increased expression of lnc-HOXB8-1:2 was accompanied by downregulation of hsa-miR-6825-5p expression and upregulation of CXCR3 protein levels. Overexpression of hsa-miR-6825-5p also reduced CXCR3 expression. lnc-HOXB8-1:2 in exosomes derived from neuroendocrine differentiated CRC cells acted as a ceRNA competitively binding hsa-miR-6825-5p to upregulate CXCR3 expression and leading to TAM infiltration and M2 polarization, which promotes neuroendocrine differentiated CRC progression. The online version contains supplementary material available at 10.1186/s12885-022-09926-1.
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