Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Molecular Testing Center, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
J Healthc Eng. 2022 Apr 21;2022:9121554. doi: 10.1155/2022/9121554. eCollection 2022.
Increasing evidence shows that dysfunction of noncoding RNAs is implicated in cancer. Neuroblastoma associated transcript 1 (NBAT-1) has been identified as a tumor suppressive lncRNA that is aberrantly expressed in cancers. However, the function and the underlying mechanisms of the NBAT-1 in colorectal carcinoma (CRC) remain unknown.
Gene expression was detected by RT-qPCR. The influence of NBAT-1 on CRC was evaluated by the cell counting kit-8 (CCK-8) assay and an in vivo xenograft mouse model. The possible binding of NBAT-1 to miRNAs was predicted via the miRDB online tool and confirmed by a dual-luciferase reporter assay. Protein expression was detected by western blot.
NBAT-1 expression was significantly decreased in CRC tissues, especially in patients with oxaliplatin (OXA) resistance. NBAT-1 inhibited OXA-resistant CRC cell proliferation in vitro and tumor growth in vivo. The mechanism study revealed that NBAT-1 functioned as a competing endogenous RNA (ceRNA) of miR-4504. NBAT-1 bound miR-4504 and decreased miR-4504 expression in CRC cells. Furthermore, WW-and-C2-domain-containing protein family member 3 (WWC3) was identified as a target of miR-4504. Downregulation of NBAT-1 promoted miR-4504 expression and reduced the level of WWC3. Inhibition of WWC3 by NBAT-1 depletion inactivated Hippo signalling by inhibiting the phosphorylation of large tumor suppressor kinase 1 (LATS1) and yes-associated protein (YAP). Consistently, knockdown of NBAT-1 suppressed the expression of YAP transcriptional targets.
These findings demonstrated that lncRNA NBAT-1 suppresses OXA-resistant CRC cell growth via inhibition of miR-4504 to regulate the WWC3/LATS1/YAP axis.
越来越多的证据表明，非编码 RNA 的功能障碍与癌症有关。神经母细胞瘤相关转录物 1（NBAT-1）已被确定为一种肿瘤抑制性 lncRNA，在癌症中异常表达。然而，NBAT-1 在结直肠癌（CRC）中的功能和潜在机制尚不清楚。
通过 RT-qPCR 检测基因表达。通过细胞计数试剂盒-8（CCK-8）测定和体内异种移植小鼠模型评估 NBAT-1 对 CRC 的影响。通过 miRDB 在线工具预测 NBAT-1 与 miRNAs 的可能结合，并通过双荧光素酶报告基因测定进行验证。通过 Western blot 检测蛋白表达。
NBAT-1 在 CRC 组织中表达明显下调，尤其是在奥沙利铂（OXA）耐药的患者中。NBAT-1 抑制了体外 OXA 耐药 CRC 细胞的增殖和体内肿瘤的生长。机制研究表明，NBAT-1 作为 miR-4504 的竞争性内源性 RNA（ceRNA）发挥作用。NBAT-1 与 miR-4504 结合并降低 CRC 细胞中的 miR-4504 表达。此外，WW 和 C2 结构域包含蛋白家族成员 3（WWC3）被鉴定为 miR-4504 的靶标。NBAT-1 的下调通过抑制大肿瘤抑制激酶 1（LATS1）和 yes 相关蛋白（YAP）的磷酸化来激活 Hippo 信号通路，从而促进 miR-4504 的表达并降低 WWC3 的水平。抑制 WWC3 通过 NBAT-1 耗竭抑制 YAP 转录靶基因的表达。
这些发现表明，lncRNA NBAT-1 通过抑制 miR-4504 抑制 OXA 耐药 CRC 细胞生长，从而调节 WWC3/LATS1/YAP 轴。
