Department of Gastroenterology & Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing, China.
Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China.
Clin Transl Gastroenterol. 2024 Mar 1;15(3):e00682. doi: 10.14309/ctg.0000000000000682.
The aim of this study was to investigate the epigenetic regulation and underlying mechanism of NRIP3 in colorectal cancer (CRC).
Eight cell lines (SW480, SW620, DKO, LOVO, HT29, HCT116, DLD1, and RKO), 187 resected margin samples from colorectal cancer tissue, 146 cases with colorectal adenomatous polyps, and 308 colorectal cancer samples were used. Methylation-specific PCR, Western blotting, RNA interference assay, and a xenograft mouse model were used.
NRIP3 exhibited methylation in 2.7% (5/187) of resected margin samples from colorectal cancer tissue, 32.2% (47/146) of colorectal adenomatous polyps, and 50.6% (156/308) of CRC samples, and the expression of NRIP3 was regulated by promoter region methylation. The methylation of NRIP3 was found to be significantly associated with late onset (at age 50 years or older), poor tumor differentiation, lymph node metastasis, and poor 5-year overall survival in CRC (all P < 0.05). In addition, NRIP3 methylation was an independent poor prognostic marker ( P < 0.05). NRIP3 inhibited cell proliferation, colony formation, invasion, and migration, while induced G1/S arrest. NRIP3 suppressed CRC growth by inhibiting PI3K-AKT signaling both in vitro and in vivo . Methylation of NRIP3 sensitized CRC cells to combined PI3K and ATR/ATM inhibitors.
NRIP3 was frequently methylated in both colorectal adenomatous polyps and CRC. The methylation of NRIP3 may potentially serve as an early detection, late-onset, and poor prognostic marker in CRC. NRIP3 is a potential tumor suppressor. NRIP3 methylation is a potential synthetic lethal marker for combined PI3K and ATR/ATM inhibitors.
本研究旨在探讨 NRIP3 在结直肠癌（CRC）中的表观遗传调控及其潜在机制。
使用了 8 种细胞系（SW480、SW620、DKO、LOVO、HT29、HCT116、DLD1 和 RKO）、187 份结直肠癌症组织的切缘样本、146 例结直肠腺瘤性息肉和 308 例结直肠癌样本。采用甲基化特异性 PCR、Western blot、RNA 干扰实验和异种移植小鼠模型进行研究。
NRIP3 在 2.7%（5/187）的结直肠癌症组织的切缘样本、32.2%（47/146）的结直肠腺瘤性息肉和 50.6%（156/308）的 CRC 样本中存在甲基化，且 NRIP3 的表达受启动子区域甲基化调控。NRIP3 的甲基化与 CRC 的晚期发病（50 岁及以上）、肿瘤分化不良、淋巴结转移和不良的 5 年总生存率显著相关（均 P<0.05）。此外，NRIP3 甲基化是独立的不良预后标志物（P<0.05）。NRIP3 抑制细胞增殖、集落形成、侵袭和迁移，同时诱导 G1/S 期阻滞。NRIP3 通过抑制 PI3K-AKT 信号通路，在体外和体内均抑制 CRC 生长。NRIP3 的甲基化使 CRC 细胞对联合 PI3K 和 ATR/ATM 抑制剂敏感。
NRIP3 在结直肠腺瘤性息肉和 CRC 中均频繁发生甲基化。NRIP3 的甲基化可能成为 CRC 的早期检测、晚期发病和不良预后标志物。NRIP3 是一种潜在的肿瘤抑制因子。NRIP3 甲基化是联合使用 PI3K 和 ATR/ATM 抑制剂的潜在合成致死性标志物。
