Published online Dec 27, 2021. doi: 10.4254/wjh.v13.i12.2137
Peer-review started: May 4, 2021
First decision: June 16, 2021
Revised: June 21, 2021
Accepted: October 27, 2021
Article in press: October 27, 2021
Published online: December 27, 2021
Stem cell autophagy disruption is responsible for the development of hepatocellular carcinoma (HCC). Many non-coding RNAs are linked to the activation and inhibition of certain genes. The SQSTM1 gene controls stem cell autophagy as shown in previous studies. The upregulation of SQSTM1 is associated with the inhibition of autophagy in cancerous stem cells in patients with HCC.
To determine whether serum microRNA, hsa-miR-519d, is linked to SQSTM1 gene and whether they could be used as diagnostic biomarkers for early-stage HCC.
In silico analysis was performed to determine the most correlated genes of autophagy with microRNAs. SQSTM1 and hsa-miR-519d were validated through this pilot clinical study. This study included 50 Egyptian participants, who were classified into three subgroups: Group 1 included 34 patients with early-stage HCC, Group 2 included 11 patients with chronic liver disease, and Group 3 (control) included 5 healthy subjects. All patients were subjected to full laboratory investigations, including viral markers and alpha-fetoprotein (AFP), abdominal ultrasound, and clinical assessment with the Child–Pugh score calculation. Besides, the patients with HCC underwent triphasic computed tomography with contrast to diagnose and determine the tumor site, size, and number. Quantitative real-time polymerase chain reaction was used to assess hsa-miR-519d-3p and SQSTM1 in the serum of all the study participants.
Hsa-miR-519d-3p was significantly upregulated in patients with HCC compared with those with chronic liver disease and healthy subjects with an area under the curve (AUC) of 0.939, with cutoff value 8.34, sensitivity of 91.2%, and specificity of 81.8%. SQSTM1 was upregulated with an AUC of 0.995, with cutoff value 7.89, sensitivity of 97.1%, and specificity of 100%. AFP significantly increased in patients with HCC with an AUC of 0.794, with cutoff value 7.30 ng/mL, sensitivity of 76.5%, and specificity of 72.7%.
This study is the first to show a direct relation between SQSTM1 and hsa-miR-519d-3p; they are both upregulated in HCC. Thus, they could be used as surrogate diagnostic markers for stem cell autophagy disturbance in early-stage HCC.
Core Tip: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. HCC is associated with poor prognosis due to difficult discovery at an early stage. The molecular pathophysiology behind HCC is not yet fully understood. Autophagy is one of the important affected pathways in HCC pathogenesis. In this study we used in silico analysis to determine a new molecular pathway and find the underlying background controlling genetic and epigenetic pathways. We found that autophagy-controlling gene SQSTM1 is related to hsa-miR-519d-3p. Also, we found that their use as early detecting biomarkers for HCC diagnosis are more efficient than the currently used alpha-fetoprotein.