Antitumor Activity of lncRNA NBAT-1 via Inhibition of miR-4504 to Target to WWC3 in Oxaliplatin-Resistant Colorectal Carcinoma.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.