Exosome-derived lnc-HOXB8-1:2 induces tumor-associated macrophage infiltration to promote neuroendocrine differentiated colorectal cancer progression by sponging hsa-miR-6825-5p

• Published in: BMC cancer Vol. 22; no. 1; pp. 1 - 928
• Main Authors: Li, Xiaojun, Lan, Qiusheng, Lai, Wei, Wu, Heng, Xu, Heyang, Fang, Kai, Chu, Zhonghua, Zeng, Yujie
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 27-08-2022; BioMed Central; BMC
• Subjects: Analysis; Antibodies; Bioinformatics; Care and treatment; Cell adhesion & migration; Cell culture; Cell differentiation; Cell growth; Chemokines; Cloning; Colon cancer; Colorectal cancer; Colorectal carcinoma; CXCR3 protein; Development and progression; Exosome; Exosomes; Fluorescence in situ hybridization; Gene expression; Health aspects; Immunofluorescence; Immunohistochemistry; Infiltration; Leukocyte migration; lnc-HOXB8-1:2; Macrophages; Medical prognosis; Membranes; Metastases; Metastasis; Neuroendocrine differentiation; Next-generation sequencing; Non-coding RNA; Patients; Prevention; Proteins; Risk factors; Surgery; Tumor-associated macrophage; Tumors; China
• ISSN: 1471-2407; 1471-2407
• DOI: 10.1186/s12885-022-09926-1

Introduction 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. Materials and methods 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. Results 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. Conclusion 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. Keywords: Colorectal cancer, Neuroendocrine differentiation, Exosome, lnc-HOXB8-1:2, Tumor-associated macrophage