Published online Nov 14, 2019. doi: 10.3748/wjg.v25.i42.6322
Peer-review started: September 3, 2019
First decision: October 14, 2019
Revised: October 29, 2019
Accepted: November 7, 2019
Article in press: November 7, 2019
Published online: November 14, 2019
Nonalcoholic steatohepatitis (NASH)-related cirrhosis is one of the liver complications in type 2 diabetes mellitus (T2DM) and is reported to be a risk factor for developing hepatocellular carcinoma (HCC). As such, a reliable screening biomarker of liver cirrhosis (LC) and HCC among T2DM patients will be important to reduce the morbidity and mortality of this disease. MicroRNA (miRNA) is considered a key player in HCC and T2DM, and it might be a hidden culprit in diabetes-associated HCC, which makes it a promising reliable prognostic tool.
The current study aimed to investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients, to reduce the morbidity and mortality from HCC among diabetic patients.
The main study objective was the identification of high-sensitivity biomarkers for detection of HCC in high-risk individuals. The present study was undertaken to identify and then validate a panel (of seven) serum miRNAs as potential biomarkers for HCC among T2DM patients.
Expression profiles of miRNAs in serum samples of diabetic LC and diabetic HCC patients were assessed using Illumina sequencing, then RT-qPCR was used to validate the significantly altered miRNAs between the two groups. Candidate miRNAs were tested in serum samples of 200 T2DM patients, 270 LC patients, 200 HCC patients and 225 healthy control subjects. Additionally, receiver operating characteristic (ROC) analysis was performed to assess the diagnostic performance of the screened miRNAs for discriminating HCC from LC and nonmalignant patients (LC + T2DM).
Expression of the sequenced miRNAs in serum was different in HCC patients vs LC and nonmalignant patients. Two miRNAs (miR-34a, miR-221) were significantly up-regulated and five miRNAs (miR-16, miR-23-3p, miR-122-5p, miR-198, miR-199a-3p) were significantly down-regulated in HCC patients compared to LC patients. Analysis of the ROC curve demonstrated that the combination of these seven miRNAs can be used as a reliable biomarker panel for detection of HCC in diabetic patients, as it could identify, with high diagnostic accuracy, HCC in diabetic LC patients [area under the curve (AUC) of 0.993] and in diabetic nonmalignant patients (AUC of 0.961). The study findings support further research to shed light on a possible role of c-Met in T2DM-associated HCC via a miRNA regulatory pathway.
This study validates a panel of serum miRNAs that can be used as a reliable noninvasive screening biomarker of HCC among T2DM cirrhotic and noncirrhotic patients. Specifically, this study shed light on a new candidate panel of miRNAs that might serve in the diagnosis of HCC among diabetic patients. Furthermore, its findings from the miRNA screening suggest a possible role of c-Met in modulating HCC in T2DM patients. The current study aimed to investigate the signature of serum miRNAs as early biomarkers for the screening of HCC among diabetic patients, to reduce the morbidity and mortality from HCC among diabetic patients. It identified a new possible reliable panel that could be developed as a screening tool for patients. In addition, it provided evidence of a new correlation of miRNA with HCC susceptibility and hepatic disease progression in diabetic patients, especially the T2DM patients. Ultimately, however, it provided evidence to support the utility of screening miRNA in diabetes-associated HCC patients. Importantly, this study identified a miRNA-specific signature in diabetes-associated HCC patients. Our hypothesis of miRNAs comprising a signature through HCC development in diabetic patients was confirmed. The implications of our findings include that the identified miRNA panel may be useful for inclusion in the screening markers for T2DM patients with nonalcoholic fatty liver disease/NASH who are at risk of developing HCC.
Diabetic patients with dysregulated miRNA could be at high risk of developing HCC compared to nondiabetic patients. Future research should investigate the effect of c-Met dysregulation on the current panel in healthy vs disease-related patients. These investigations of the molecular mechanism of this miRNA interaction with c-Met should be carried out via a specific knock-out assay.