Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Abstract

Betulinic acid (BA) is a natural product extracted from a broad range of medicinal and edible herbal plants. Previous studies showed that BA induces cell death in tumors derived from multiple tissues; however, the underlying mechanism remains obscure. The present study aimed to study the effects of BA on autophagy and apoptosis of hepatocellular carcinoma (HCC). Human HCC cell lines and orthotopic HCC implanted mice were employed to examine the BA‐induced tumor suppression; RT 2 long noncoding RNA (lncRNA) PCR array and database analysis were used to explore the possible mechanisms; validation of pathways was performed using siRNA and miRNA inhibitors. The results indicated that BA regulated autophagy and induced apoptosis in HCC. The degradation of inhibitor of apoptosis proteins (IAPs), the conversion of LC3‐I to LC3‐II, and p62 accumulation were enhanced by BA, thereby suggesting that the downregulation of IAPs and autophagic cell death are induced by BA. The addition of autophagy and lysosomal inhibitors indicated that BA induced autophagy‐independent apoptosis via degradation of IAPs. Moreover, RT 2 lncRNA PCR array and database analysis suggested that BA downregulated the levels of lncRNA MALAT1, which is considered to be an oncogene. Further investigations demonstrated that lncRNA MALAT1 functioned as a ceRNA (competing endogenous RNA) to contribute to BA‐mediated degradation of IAPs by sponging miR‐22‐3p. Therefore, BA could be developed as a potential anticancer agent for HCC.

Combination Treatment With Inhibitors of ERK and Autophagy Enhances Antitumor Activity of Betulinic Acid in Non–small-Cell Lung Cancer In Vivo and In Vitro

“…It has been reported that BA also can induce cell autophagy, which results in either cell death or survival ( Li et al, 2019 ; Chen et al, 2020 ). Increasing evidence highlights that cancer cells have the ability to harness autophagy to thrive ( Galluzzi et al, 2017 ).…”

“…Phytochemicals are biologically active compounds isolated from plants or herbs, which are recognized as potent anticarcinogenic agents ( Yin et al, 2017 ; Ng et al, 2018 ; Chen et al, 2020 ). Betulinic acid (BA, (3β)-3-hydroxyl-lup-20 (29)-en-28-oic acid, the chemical structure of BA shown in Figure 9G ) is a naturally lupane-structured pentacyclic triterpenoid that is mainly widespread in white-barked birch trees ( Zhang et al, 2015 ).…”

Inhibition of SREBP-1 Activation by a Novel Small-Molecule Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Tissue to Radiofrequency Ablation

“…For these inhibitors, the main research report is to inhibit the activity of SREBP-1 as a tool in metabolism-related research. Betulin can exert anti-tumor activity in HCC (78)(79)(80). Pseudoprotodioscin and Fatostatin have been less studied in HCC, but it has also been clearly reported in other tumor types (81)(82)(83)(84).…”

The role of ceRNA-mediated diagnosis and therapy in hepatocellular carcinoma

“…Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) is one of the most widely studied lncRNAs in cancer therapy. lncRNA MALAT1 was found to play an oncogenic role in the occurrence and development of HCC and act as a proto-oncogene to regulate the expression of apoptosis inhibitor IAPS [ 128 ]. MALAT1 can act as the ceRNA of miR-22-3p to cause the abnormal expression of the target gene inhibitor of apoptosis proteins (IAPs) [ 129 ].…”