Development of a Non‐Coding‐RNA‐based EMT/CSC Inhibitory Nanomedicine for In Vivo Treatment and Monitoring of HCC

Abstract

The objective of this study is to improve the overall prognosis of patients with hepatocellular carcinoma (HCC); therefore, new therapeutic methods that can be used in vivo are urgently needed. In this study, the relationship between the quantities of microRNA (miR)‐125b‐5p in clinical specimens and clinicopathological parameters is analyzed. A folate‐conjugated nanocarrier is used to transfect miR‐125b‐5p in vivo and to observe the therapeutic effect on HCC. The inhibitory effect and mechanism of miR‐125b‐5p on hepatoma cells are also studied. Data from clinical specimens and in vitro experiments confirm that the miR‐125b‐5p quantity is negatively correlated with progression, and the target protein that regulates the epithelial–mesenchymal transition (EMT)/cancer stem cells (CSC) potential in HCC is STAT3. The miR‐125b‐5p/STAT3 axis inhibits the invasion, migration, and growth of HCC via inactivation of the wnt/β‐Catenin pathway. miR‐125b‐5p‐loaded nanomedicine effectively inhibits the EMT/CSC potential of hepatoma cells in vivo together with their magnetic resonance imaging (MRI) visualization characteristics. An HCC‐therapeutic and MRI‐visible nanomedicine platform that achieves noninvasive treatment effect monitoring and timely individualized treatment course adjustment is developed.

Targeting STAT3 in Cancer Immunotherapy

“…), thereby modulating STAT3 expression and activation [ 8 , 25 – 29 ]. For instance, miR-125b-5p can directly target STAT3 and inhibit its expression [ 27 ], while miR-218 indirectly suppresses STAT3 activation by targeting IL-6 receptor and JAK3 [ 28 ]. More recently, it has shown that exosome-mediated transfer of certain miRNAs, such as miR-193a-3p, miR-210-3p and miR-5100, can promote metastasis of lung cancer by enhancing STAT3 activity [ 29 ], although the molecular mechanisms await further investigation.…”

Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development

“…AuNPs MAPK signalling Inhibited the proliferation of SKOV3 (ovarian) cancer cells and delayed the tumoral and metastases growth by reversing EMT and inhibition of MAPK signalling [27] PEI coated SPIONs Src kinase, miR-21, MMP2 Reduced the invadosome intensity and decreased the ability of Pan02 (pancreatic cancer) cells to invade through basement membrane. [28] FA-PEG-PEI-SPIONs miR-125b-5p JAK-STAT, Wnt/β-Catenin Inhibited the invasion, migration, and growth of HCC HUH7 and HCCLM3 cells [29] Zinc…”

“…Guo et al (2019) loaded miR-125-5p into a folate acid coated Fa-polyethyleneglycol (PEG)-g-polyetherimide (PEI) superparamagnetic iron oxide nanocarrier (SPIONs), evaluating its therapeutic effect against hepatocellular carcinoma (HCC). The authors reported that the miR-125-5p loaded nanomedicine effectively inhibited the EMT potential of HCC cells via the inhibition of STAT and the inactivation of Wnt/β-Catenin, inhibiting tumour growth in HCC-bearing mice [29]. Similar work by Huang et al (2019) demonstrated that silica-coated zinc arsenite NPs (ZnAs@SiO 2 NPs) significantly inhibited the proliferation, migration and invasion of HCC cell lines, attenuating in vivo tumour growth by 2.2-fold in comparison to NP-only control, mediated through the upregulation of SH2-containing protein tyrosine phosphatase 1 (SHP-1) and the corresponding suppression of JAK2/STAT3 signalling [30].…”

Long noncoding RNA MAPKAPK5-AS1 promotes colorectal cancer progression by cis-regulating the nearby gene MK5 and acting as a let-7f-1-3p sponge

“…A previous report demonstrated that lncRNA UICLM (upregulated in colorectal cancer liver metastasis) expression in CRC promoted tumor growth and liver metastasis, and knockdown of lncRNA UICLM expression impaired cell sphere-forming ability and epithelial-mesenchymal transformation (EMT) [21,22]. EMT is an important biological process of malignant tumor cells derived from epithelial cells to obtain the ability to migrate and invade [23]. In 2000, the zinc nger factor snail (Snail Homologue 1), hereinafter referred to as SNAI1, is a transcriptional suppressor that seems to control protein stability, nuclear localization and function by phosphorylation and zinc transport proteins.…”