MiR-106b inhibitors sensitize TRAIL-induced apoptosis in hepatocellular carcinoma through increase of death receptor 4

Abstract

TNF-related apoptosis-inducing ligand (TRAIL), which is a member of the TNF superfamily, can induce tumor cell apoptosis. However, multiple types of tumor, including hepatocellular carcinoma, show tolerance to TRAIL. Previous studies have demonstrated that tumor cells usually change their expression profile of microRNA (miRNA) to obtain the ability of tolerance to drugs. However, whether such change of miRNA on TRAIL sensitivity is seen in hepatocellular carcinoma still needs to be explored. In this study, we observed overexpression of miR-106b in both HCC patients’ tumor tissues and cell lines. Furthermore, we found that overexpression of miR-106b is associated with the sensitivity of TRAIL to HCC. Silencing of miR-106b with antisense oligonucleotide (anti-miR-106b) is proved to enhance the TRAIL-induced apoptosis and reduce the acquired drug resistance to TRAIL in HCC. Mechanically, we didn't observe the obvious change of pro-apoptotic proteins (Bax and Bid) and anti-apoptotic proteins (Bcl-2, Mcl-1 and Bcl-xl) after treatment of anti-miR-106b. However, we used the methods of bioinformatics, flow cytometry, cellular and molecular methods to prove that miR-106b directly targeted to death receptor 4 (DR4) 3′-UTR (3′-Untranslated Regions). MiR-106b inhibitors induced increase of DR4 expression and therefore enhancing TRAIL-mediated apoptosis in HCC. In summary, these results suggest the application of miR-106b inhibitors in HCC treatment. Combination with miR-106b inhibitors and TRAIL may be a novel clinical treatment method on HCC treatment in the future.

miR-494 Sensitizes Gastric Cancer Cells to TRAIL Treatment Through Downregulation of Survivin

“…6C) in the presence of cytochrome c [28]. As the results, although miR-494 failed to promote the activation of caspase-8 which is the substrate of TRAIL-DR4/DR5 complex [11], it increased the activation of caspase-9 and caspase-3 in the TRAIL-treated gastric cancer cells (Fig. 6D).…”

“…Since TRAIL-triggered cell death is dependent on the activation of TRAIL-DR4/DR5 signaling [11], we next investigated whether miR-494 changed the expression of DR4 or DR5 in gastric cancer cells. However, we did not observe obvious change of DR4 or DR5 expression in BGC-823 and MGC-803 cells when they were treated with miR-494 (Fig.…”

“…Subsequently, caspase-8 is triggered followed by induction of mitochondria collapse [9][10][11]. As the downstream incidence of mitochondria collapse, some mitochondria-derived apoptosis inducers such as cytochrome c and AIF were released into the cytoplasm [40,41].…”

“…In TRAIL-dependent pathway, TRAIL binds to death receptor 4 (DR4) and death receptor 5 (DR5) followed by recruitment of procaspase-8 to form the deathinducing signaling complex (DISC). Subsequently, caspase-8 was activated and mitochondrial apoptosis occurs [9][10][11]. As TRAIL-induced cytotoxicity shows high specificity to cancer cells, it is considered as a novel and low-toxic anti-tumor drug used for various cancers [12,13].…”

miR-128 Targets the SIRT1/ROS/DR5 Pathway to Sensitize Colorectal Cancer to TRAIL-Induced Apoptosis

“…TRAIL binds to death receptors 5 (DR5) located on the surface of cancer cells, and thus activates caspase-8-dependent apoptosis [7][8][9]. By contrast, treatment with TRAIL has no effect on normal tissues [10].…”