MiR‐378a‐3p was identified and validated as a biomarker for HCC diagnosis and prognosis, it was shown independently regulated several important transcription factors including PLAGL2 and β‐catenin, then affected the β‐catenin signaling, which could be the potential mechanism for its function as a tumor suppressor and its abnormal expression could affect the cell growth and invasion of HCC. The gene discussed is PLAGL2; the disease is hepatocellular carcinoma.