miR-19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4: validation by bioinformatics and experimental analyses

Background: As a disease with extremely complex molecular mechanisms, many deregulated miRNAs have been identified in colon Cancer. Few studies have been performed by using Ingenuity Pathways Analysis (IPA) to predict miRNAs specifically expressed in colon Cancer.

Methods: A characteristic microRNA-target network of colon Cancer was explored using IPA. Then the clinical significance of miR-19b-3p was evaluated in 211 colon Cancer patients. The roles of miR-19b-3p and its candidate target gene, SMAD4, in colon Cancer progression were examined both in vitro and in vivo.

Results: Bioinformatics analysis showed that 15 MicroRNAs screened by IPA were significantly correlated with malignant biological behaviors of colon Cancer. miR-19b-3p was the most significantly upregulated candidate based on the validation experiment using 211 colon Cancer samples. High expression of miR-19b-3p was significantly associated with high N stage (P < 0.001), high AJCC stage (P < 0.001), poor histologic grade (P = 0.032), frequent venous and lymphatic invasion (P = 0.027), and liver metastasis (P < 0.001). Survival analysis revealed that miR-19b-3p was an independent prognostic factor associated with colon Cancer patient's overall survival (OS) and disease-free survival (DFS). miR-19b-3p promoted proliferation and chemoresistance of colon Cancer cells, but had no effect on invasion in vitro, along with tumorigenesis in vivo. In addition, we confirmed that miR-19b-3p mediates resistance to oxaliplatin-based chemotherapy via SMAD4.

Conclusions: Our findings demonstrate the role of miR-19b-3p-SMAD4 axis in colon Cancer progression, which may become a potential therapeutic target against chemotherapy resistance.