Department of Pathology and Women's Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, China.
Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of Chinese Academy of Medical Sciences (2019RU042), Zhejiang University School of Medicine, Hangzhou, China.
Cancer Immunol Res. 2022 Sep 1;10(9):1095-1110. doi: 10.1158/2326-6066.CIR-21-1011.
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.
MIR4435-2HG，也称为 LINC00978，先前被描述为致癌的长非编码 RNA（lncRNA）。然而，我们在这里表明，Mir4435-2hg 耗竭促进了结肠炎相关结直肠癌、自发性肠腺瘤性息肉病和皮下肿瘤的体内模型中的结直肠肿瘤发生和进展。改变结直肠癌细胞中的 MIR4435-2HG 并没有改变细胞增殖、迁移或侵袭的潜力。RNAscope 检测表明，大多数 MIR4435-2HG 位于肿瘤基质中，这导致结直肠癌肿瘤组织中 MIR4435-2HG 的高表达。野生型和 Mir4435-2hg 缺陷型小鼠结直肠癌组织的转录组分析显示，Mir4435-2hg 是一种肿瘤抑制基因，它调节免疫微环境。Mir4435-2hg 的缺失导致中性粒细胞减少和多形核髓源性抑制细胞（PMN-MDSC）升高。在组织特异性 Mir4435-2hg 敲除小鼠中，我们证实 Mir4435-2hg 耗竭在中性粒细胞中，而不是在肠上皮细胞中，促进了结直肠癌的进展。从机制上讲，Mir4435-2hg 耗竭通过扰乱 PMN-MDSC 的脂肪酸代谢增强了其免疫抑制能力。这些发现表明，MIR4435-2HG 是一种肿瘤抑制性 lncRNA，其缺失可能增加肿瘤浸润性 PMN-MDSC，并增强 PMN-MDSC 的免疫抑制潜力，从而促进结直肠癌的发生。这为进一步阐明结直肠癌的发病机制和提供潜在的抗肿瘤免疫治疗靶点提供了理论依据。
