MicroRNAs Related to TACE Treatment Response: A Review of the Literature from a Radiological Point of View

Abstract

Hepatocellular Carcinoma (HCC) is the sixth most common cancer in the world. Patients with intermediate stage (Barcelona Clinic Liver Cancer, B stage) hepatocellular carcinoma (HCC) have been able to benefit from TACE (transarterial chemoembolization) as a treatment option. MicroRNAs (miRNAs), i.e., a subclass of non-coding RNAs (ncRNAs), participate in post-transcriptional gene regulation processes and miRNA dysfunction has been associated with apoptosis resistance, cellular proliferation, tumor genesis, and progression. Only a few studies have investigated the role of miRNAs as biomarkers predicting TACE treatment response in HCC. Here, we review the studies' characteristics from a radiological point of view, also correlating data with radiological images chosen from the cases of our institution.

Keywords: biomarkers; hepatocellular carcinoma (HCC); liver; liver cirrhosis; liver tumor; microRNA (miRNA); prognostic biomarkers; transarterial chemoembolization (TACE); treatment response criteria.

Figure 1

The biogenesis of miRNAs. miRNAs’ genes are transcribed by RNA polymerase II into a pri-miRNA containing one to six miRNA precursors. The double-strand RNA structure is recognized by a nuclear protein called Pasha (DGCR8), which binds the enzyme Drosha to release the pre-microRNA. Pre-miRNAs are exported from the nucleus to the cytoplasm using the shuttle of Exportin-5. Once in the cytoplasm, the pre-miRNA is cleaved by the RNase III Dicer, which interacts with the 3′-end and cuts the loop joining the 3′- and 5′-arms, producing a yet-not-final miRNA duplex (about 22 nucleotides in length). One strand of the mature miRNA is usually degraded, whereas one strand will become a mature miRNA bound to an RNA-mediated silencing complex (RISC). In this complex, the mature miRNA targets the 3′-UTR region of its target mRNA to regulate its translation.

Figure 2

Seventy-two-year-old man with HCC undergoes TACE procedure: selective angiography (a) demonstrates a hypervascular mass in segment VIII (arrow) supplied by a hepatic artery branch (arrowhead); (b) after transarterial chemoembolization (TACE), a reduction of the size of the lesion is appreciated (arrow); selective angiography of the branch of the left hepatic artery (c) supplying the same lesion shows persistent enhancing tumor (arrow); and angiography after another injection of doxorubicin and synthetic microspheres (d) where the lesion is no longer visible.

Figure 3

Hepatocellular carcinoma treated with transarterial chemoembolization (TACE) with complete response. After TACE, no residual enhancement is seen in the arterial phase on contrast-enhanced CT scan (a) and ultrasound (b).

Figure 4

Hepatocellular carcinoma treated with transarterial chemoembolization (TACE) with a complete response: pre-treatment contrast-enhanced CT (a,b) shows a 12 mm nodule (arrow) in segment 7 with arterial enhancement (a) and late wash-out (b). After TACE (c,d), no residual enhancement is seen in the arterial phase (arrowhead in (c)) and there is no wash-out in the late phase (arrowhead in (d)). A geographic region of altered enhancement surrounding the treated lesion in the arterial phase (*) is considered normal.

Figure 5

Hepatocellular carcinoma treated with transarterial chemoembolization (TACE) with partial response. Pre-treatment contrast-enhanced CT (a,b) shows a 24 mm nodule (arrow) in segment 8 with arterial hyper-enhancement (a) and late wash-out (b). After TACE (c,d), the presence of nodular hyper-enhancement in the arterial phase (arrow in (c)) with wash-out in the late phase (arrow in (d)) demonstrate the residual viable tumor consistent with a partial response to treatment.

Figure 6

Heatmap with the pseudo-color scale underneath the differentially expressed miRNAs. Log2-transformed microarray signal is considered in the comparison between complete responder (CR; blue bar), partial responder, and progressive diseases (PRPD; red bar) patients. Unsupervised hierarchical clustering was used to order miRNAs. The sample tree with optimized leaf-ordering was drawn using Euclidean distances and average linkages for cluster-to-cluster distance. CR = complete responder and PRPD = partial responder and progressive diseases.

Figure 7

Complete response. Seventy-seven-year-old man, affected with HCC, expresses high miR-4492 levels at the time of diagnosis and undergoes TACE procedure: (a) selective angiography shows a hypervascular mass in segment VIII (arrow); (b) after TACE, the lesion was no longer visible; and (c) after the procedure, (c,d), no residual enhancement is seen in the arterial phase and there is no wash-out in the late phase. A geographic region of altered enhancement surrounding the treated lesion in the arterial phase (arrow) is considered normal.

Figure 8

Partial response. Sixty-five-year-old man, affected with HCC, expresses low miR-4492 levels at the time of diagnosis and undergoes TACE procedure: (a) pre-treatment arterial contrast-enhanced CT shows a 22 mm nodule (arrow) in segment 8 with arterial hyper-enhancement; (b) selective angiography confirms a hypervascular mass in segment VIII (arrow); (c) after TACE, the lesion was no longer visible; and (d) one month after the procedure, the presence of nodular hyper-enhancement in the arterial phase (arrow) demonstrates the residual viable tumor consistent with a partial response to treatment.