Dai Shipeng, Xu Fan, Xu Xiaozhang, Huang Tian, Wang Yiming, Wang Hongyu, Xie Yucheng, Yue Lei, Zhao Wenhu, Xia Yongxiang, Gu Jian, Qian Xiaofeng
Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, Jiangsu Province, China.
Hangzhou Institute of Medicine (HIM), Zhejiang Cancer Hospital, Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
Cancer Cell Int. 2024 Jul 5;24(1):235. doi: 10.1186/s12935-024-03422-1.
Colorectal cancer is among the most common malignant tumors affecting the gastrointestinal tract. Liver metastases, a complication present in approximately 50% of colorectal cancer patients, are a considerable concern. Recently, studies have revealed the crucial role of miR-455 in tumor pathogenesis. However, the effect of miR-455 on the progression of liver metastases in colorectal cancer remains controversial. As an antagonist of bone morphogenetic protein(BMP), Gremlin 1 (GREM1) may impact organogenesis, body patterning, and tissue differentiation. Nevertheless, the role of miR-455 in regulating GREM1 in colorectal cancer liver metastases and how miR-455/GREM1 axis influences tumour immune microenvironment is unclear.
Bioinformatics analysis shows that miR-455/GREM1 axis plays crucial role in liver metastasis of intestinal cancer and predicts its possible mechanism. To investigate the impact of miR-455/GREM1 axis on the proliferation, invasion, and migration of colorectal cancer cells, colony formation assay, wound healing and transwell assay were examined in vitro. The Dual-Luciferase reporter gene assay and RNA pull-down assay confirmed a possible regulatory effect between miR-455 and GREM1. In vivo, colorectal cancer liver metastasis(CRLM) model mice was established to inquiry the effect of miR-455/GREM1 axis on tumor growth and macrophage polarization. The marker of macrophage polarization was tested using immunofluorescence(IF) and quantitative real-time polymerase chain reaction(qRT-PCR). By enzyme-linked immunosorbent assay (ELISA), cytokines were detected in culture medium supernatants.
We found that miR-455 and BMP6 expression was increased and GREM1 expression was decreased in liver metastase compared with primary tumor. miR-455/GREM1 axis promotes colorectal cancer cells proliferation, migration, invasion via affected PI3K/AKT pathway. Moreover, downregulating GREM1 augmented BMP6 expression in MC38 cell lines, inducing M2 polarization of macrophages, and promoting liver metastasis growth in CRLM model mice.
These data suggest that miR-455/GREM1 axis promotes colorectal cancer progression and liver metastasis by affecting PI3K/AKT pathway and inducing M2 macrophage polarization. These results offer valuable insights and direction for future research and treatment of CRLM.
结直肠癌是影响胃肠道的最常见恶性肿瘤之一。肝转移是约50%的结直肠癌患者会出现的一种并发症，是一个相当令人担忧的问题。最近，研究揭示了miR - 455在肿瘤发病机制中的关键作用。然而，miR - 455对结直肠癌肝转移进展的影响仍存在争议。作为骨形态发生蛋白（BMP）的拮抗剂，Gremlin 1（GREM1）可能影响器官发生、身体模式形成和组织分化。然而，miR - 455在结直肠癌肝转移中调节GREM1的作用以及miR - 455 / GREM1轴如何影响肿瘤免疫微环境尚不清楚。
生物信息学分析表明，miR - 455 / GREM1轴在肠癌肝转移中起关键作用，并预测其可能的机制。为了研究miR - 455 / GREM1轴对结直肠癌细胞增殖、侵袭和迁移的影响，在体外进行了集落形成试验、伤口愈合试验和Transwell试验。双荧光素酶报告基因试验和RNA下拉试验证实了miR - 455与GREM1之间可能的调节作用。在体内，建立结直肠癌肝转移（CRLM）模型小鼠，以探究miR - 455 / GREM1轴对肿瘤生长和巨噬细胞极化的影响。使用免疫荧光（IF）和定量实时聚合酶链反应（qRT - PCR）检测巨噬细胞极化的标志物。通过酶联免疫吸附测定（ELISA）检测培养基上清液中的细胞因子。
我们发现，与原发性肿瘤相比，肝转移中miR - 455和BMP6表达增加，GREM1表达降低。miR - 455 / GREM1轴通过影响PI3K / AKT途径促进结直肠癌细胞的增殖、迁移和侵袭。此外，下调GREM1可增加MC38细胞系中BMP6的表达，诱导巨噬细胞的M2极化，并促进CRLM模型小鼠的肝转移生长。
这些数据表明，miR - 455 / GREM1轴通过影响PI3K / AKT途径和诱导M2巨噬细胞极化促进结直肠癌进展和肝转移。这些结果为未来CRLM的研究和治疗提供了有价值的见解和方向。
