TSN inhibits cell proliferation, migration, invasion, and EMT through regulating miR-874/HMGB2/β-catenin pathway in gastric cancer

Abstract

Gastric cancer (GC) is the second leading cause of cancer-associated deaths worldwide. Tanshinone IIA (TSN) is the pure extract from the root of red-rooted salvia and has been reported to inhibit the progression of GC cells. In this study, we investigated the microRNA (miRNA) mediated gene repression mechanism in TSN-administrated GC condition. The cell viability of GC was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were detected by transwell assays. The expression levels of epithelial-mesenchymal transition (EMT)-associated proteins (N-cadherin, vimentin, E-cadherin), High-mobility group box proteins 2 (HMGB2), β-catenin pathway-related proteins (β-catenin, c-myc, cyclin D1) were detected by western blot analysis in TSN/GC. The expression patterns of miR-874 and HMGB2 in GC were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The potential miR-874-targeted HMGB2 was searched via bioinformatics methods and identified by dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and RNA pull-down assays. Xenograft tumor model was used to evaluate biological function in vivo. TSN limited the proliferation, migration, invasion, EMT progression in GC, and these results could be inverted by the silencing of miR-874. Moreover, the putative binding sites between miR-874 and HMGB2 were predicted by starBase software online. Meanwhile, enforced expression of HMGB2, negatively correlated with that of miR-874, reversed the positive effects of TSN administration on cells. Mechanically, TSN restrained the GC progression by miR-874/ HMGB2/β-catenin signaling in vitro. Additionally, in vivo experiments confirmed that TSN inhibited the GC progression as well. TSN restrained the GC progression by regulating miR-874/HMGB2/β-catenin pathways in vitro and in vivo.

Identification of HMGB2 associated with proliferation, invasion and prognosis in lung adenocarcinoma via weighted gene co-expression network analysis

“…HMGB2 promotes the progression of breast cancer by targeting lactate dehydrogenase B and febrile convulsions 1 proteins [10]. In gastric cancer, HMGB2 indicates a poor prognosis [11,12] and is involved in tumor progression along with microRNAs, long non-coding RNAs, and proteins [13][14][15]. HMGB2 is also considered as an oncogene in NSCLC and is involved in the chemotherapeutic drug resistance of NSCLC [16][17][18].…”

Proteomics analyses of Xiaopi granules in N‐methyl‐N′‐nitro‐N‐nitrosoguanidine–induced gastric epithelial dysplasia rat model using LC–MS

“…The study on the mechanisms of P. notoginseng and H. diffusa Willd against digestive tract cancer illustrated that its therapeutic effect might be strongly associated with apoptosis, migration, invasion, and regulation of the expression of metastasis‐associated signaling molecules (Lee et al, 2017; Liu et al, 2018). Tanshinone IIA (extracted from the root of red‐rooted salvia) can restrain gastric cancer progression by regulating miR‐874/HMGB2/β‐catenin pathways in vitro and in vivo (Yuan et al, 2020). Moreover, R. linderae and citron peel regulate the flow of qi for harmonizing the stomach and enhancing immune function.…”

miR-874: An Important Regulator in Human Diseases

“…As shown in Table 1 , miR-874 is downregulated in at least 22 human malignancies, such as colorectal cancer (CRC) ( Huang et al, 2020a ; Yu et al, 2020 ; Que et al, 2017 ; Zhao and Dong, 2016 ; Han et al, 2016 ; Wang et al, 2021 ; Zhang et al, 2021c ), gastric cancer (GC) ( Huang et al, 2018 ; Sun et al, 2020 ; Yuan et al, 2020 ; Liu et al, 2017 ; Zhang et al, 2015 ; Jiang et al, 2014 ), hepatocellular carcinoma (HCC) ( Zhang et al, 2018b ; Jiang et al, 2017 ; Leong et al, 2017 ; Song et al, 2016 ), esophageal squamous cell carcinoma (ESCC) ( Yuan et al, 2018 ), pancreatic ductal adenocarcinoma (PDAC) ( Diao et al, 2018 ), non-small cell lung cancer (NSCLC) ( Bu et al, 2020 ; Yang et al, 2017 ; Ahmad et al, 2015 ; Kesanakurti et al, 2013 ; Wang et al, 2020b ), osteosarcoma (OS) ( Tang et al, 2018 ; Liu et al, 2020 ; Dong et al, 2016 ; Ghosh et al, 2017 ), epithelial ovarian cancer (EOC) ( Xia et al, 2018 ) cervical cancer (CC) ( Liao et al, 2018 ; Liu et al, 2021a ), retinoblastoma (RB) ( Zhang et al, 2018a ; Wang et al, 2020a ), prostate cancer (PCa) ( Pashaei et al, 2017 ) maxillary sinus squamous cell carcinoma (MSCC) ( Nohata et al, 2011 ), breast cancer (BC) ( Li et al, 2020 ; Zhang et al, 2017 ; Wang et al, 2014 ), triple-negative breast cancer (TNBC) ( Wu et al, 2020 ), rhabdomyosarcoma (RMS) ( Shang et al, 2019 ), papillary thyroid carcinoma (PTC) ( Ding et al, 2021 ), endometrial cancer ( Witek et al, 2021 ), cholangiocarcinoma ( Pan et al, 2021 ), glioma ( Li et al, 2021a ), myeloma (MM) ( Tian et al, 2021 ), head and neck squamous cell carcinoma (HNSCC) ( Nohata et al, 2013 ) and acute myeloid leukemia (AML) ( Zhang et al, 2021a ).…”

“…The target genes of miR-874 are involved in at least five classical signaling pathways, including the Wnt/β-catenin pathway [TFAP2B ( Wang et al, 2020a ), CDK8 ( Yu et al, 2020 ), HMGB2 ( Yuan et al, 2020 ), CXCL12 ( Xie et al, 2020 ), and FAM84A ( Ding et al, 2021 )], the Hippo pathway [YAP1 and TAZ ( Que et al, 2017 )], the PI3K/AKT pathway [AQP3 ( Li et al, 2020 )], the JAK/STAT pathway [STAT3 ( Zhang et al, 2015 ; Li et al, 2020 ; Zhao and Dong, 2016 ; Bu et al, 2020 ; Yuan et al, 2018 ; Shang et al, 2019 )] and the Hedgehog signaling pathway [SUFU ( Lin et al, 2018 )] ( Figure 3 ).…”

“…In CRC, the circ_0005576/miR-874-3p/CDK8 axis can cause the abnormal activation of the Wnt/β-catenin signaling pathway and the proliferation of CRC cells ( Yu et al, 2020 ). In GC cell lines the downregulation of the miR-874-3p/HMGB2 axis can upregulate the expression of β-catenin, CCND1, and MYC, which shows that the abnormal activation Wnt/β-catenin signaling pathway may be regulated by the miR-874-3p/HMGB2 axis in GC ( Yuan et al, 2020 ).…”