Long Noncoding RNA MIR4435-2HG Suppresses Colorectal Cancer Initiation and Progression By Reprogramming Neutrophils.
Long Noncoding RNA MIR4435-2HG Suppresses Colorectal Cancer Initiation and Progression By Reprogramming Neutrophils.
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长非编码 RNA MIR4435-2HG 通过重编程中性粒细胞抑制结直肠癌的发生和进展
DOI：
10.1158/2326-6066.cir-21-1011
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发表时间：
2022-09-01
影响因子：
10.1
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长非编码(LNC)RNA MIR4435-2HG在结直肠癌(CRC)中对中性粒细胞/PMN-MDSCs具有调节作用。数据表明，这种lncRNA是肿瘤间质中的肿瘤抑制因子，而不是肿瘤细胞中的癌基因，这突显了结直肠癌潜在的治疗靶点。MIR4435-2HG，也被称为LINC00978，此前已被描述为致癌的长非编码RNA(LncRNA)。然而，我们在此表明，Mir4435-2HG缺失促进了结肠炎相关性结直肠癌、自发性肠腺瘤性息肉病和皮下肿瘤体内模型的结直肠癌的发生和发展。MIR4435-2HG在结直肠癌细胞中的改变不会改变细胞在体外增殖、迁移或侵袭的可能性。RNAScope分析表明，MIR4435-2HG主要定位于肿瘤间质，导致MIR4435-2HG在结直肠癌组织中高表达。对野生型和Mir4435-2HG缺陷小鼠的结直肠癌组织的转录组分析表明，Mir4435-2HG是一个肿瘤抑制基因，调节免疫微环境。Mir4435-2HG基因缺失导致中性粒细胞减少，多形核髓系来源的抑制细胞(PMN-MDSC)增加。在组织特异性Mir4435-2HG基因敲除小鼠中，我们证实了中性粒细胞中Mir4435-2HG的缺失，而不是肠上皮细胞中的Mir4435-2HG缺失，促进了结直肠癌的进展。从机制上讲，Mir4435-2HG缺失通过干扰PMN-MDSCs的脂肪酸代谢而增强其免疫抑制能力。提示MIR4435-2HG是一种抑癌基因，其缺失可增加PMN-MDSCs对肿瘤的侵袭，增强PMN-MDSCs的免疫抑制能力，从而促进结直肠癌的发生发展。这为进一步阐明结直肠癌的发病机制和潜在的抗肿瘤免疫治疗靶点提供了理论基础。
Long noncoding (lnc) RNA MIR4435-2HG can regulate neutrophils/PMN-MDSCs in colorectal cancer (CRC). Data identify this lncRNA as a tumor suppressor in the tumor stroma, rather than as an oncogene in tumor cells, highlighting a potential therapeutic target in CRC. MIR4435-2HG, also known as LINC00978, has previously been described as an oncogenic long noncoding RNA (lncRNA). However, we show here that Mir4435-2hg depletion promoted colorectal tumorigenesis and progression in in vivo models of colitis-associated colorectal cancer, spontaneous intestinal adenomatous polyposis, and subcutaneous tumors. Alteration of MIR4435-2HG in colorectal cancer cells did not change the potential for cell proliferation, migration, or invasion in vitro. RNAscope assays showed that most MIR4435-2HG was located in the tumor stroma, which caused high expression of MIR4435-2HG in colorectal cancer tumor tissue. Transcriptome analysis of colorectal cancer tissues from wild-type and Mir4435-2hg–deficient mice revealed Mir4435-2hg as a tumor suppressor gene that regulated the immune microenvironment. Loss of Mir4435-2hg led to a decline in neutrophils and elevation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). In tissue-specific Mir4435-2hg knockout mice, we confirmed that Mir4435-2hg depletion in neutrophils, but not in intestinal epithelial cells, promoted colorectal cancer progression. Mechanistically, Mir4435-2hg depletion enhanced the immunosuppressive ability of PMN-MDSCs by disturbing their fatty acid metabolism. These findings suggest that MIR4435-2HG is a tumor-suppressing lncRNA whose deficiency could increase tumor-infiltrating PMN-MDSCs and enhance the immunosuppressive potential of PMN-MDSCs to promote colorectal cancer development. This provides a theoretical basis for further illustrating the pathogenesis of colorectal cancer and a potential antitumor immunotherapy target.