High mobility group box 3 promotes cervical cancer proliferation by regulating Wnt/β-catenin pathway.
High mobility group box 3 (HMGB3) plays an important role in the development of various cancer. This study aims to explore whether HMGB3 regulates cervical cancer (CC) progression and elucidate the underlying mechanism.
HMGB3 expression in clinical patients' tumor samples were determined by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. HMGB3 overexpression/knockdown were used to investigate its function. Cell apoptosis and cycle were detected by Annexin V/PI staining and flow cytometry. In vivo tumor model was made by subcutaneous injection of HeLa cells transfected with shRNAs targeting HMGB3 (sh-HMGB31) into the flank area of nude mice. Western blot was used to detect the levels of β-catenin, c-Myc, and matrix metalloproteinase-7 (MMP-7) in Hela and CaSki cells transfected with sh-HMGB3 or shRNAs targeting β-catenin.
Both messenger RNA and protein levels of HMGB3 were upregulated in CC tissues from patients. High expression level of HMGB3 had positive correlation with serosal invasion, lymph metastasis, and tumor sizes in CC patient. Functional experiments showed that HMGB3 could promote CC cell proliferation both in vitro and in vivo. The expression levels of c-Myc and MMP-7 were increased, resulting in regulating cell apoptosis, cell cycle, and activating Wnt/β-catenin pathway.
Our data indicated that HMGB3 may serve as an oncoprotein. It could be used as a potential prognostic marker and represent a promising therapeutic strategy for CC treatment.
Zhuang S
，Yu X
，Lu M
，Li Y
，Ding N
，Ding Y
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Overexpression of miR-758 inhibited proliferation, migration, invasion, and promoted apoptosis of non-small cell lung cancer cells by negatively regulating HMGB.
Non-small cell lung cancer (NSCLC) is one of the most fatal types of cancer with significant mortality and morbidity worldwide. MicroRNAs (miRs) have been confirmed to have positive functions in NSCLC. In the present study, we try to explore the role of miR-758 in proliferation, migration, invasion, and apoptosis of NSCLC cells by regulating high-mobility group box (HMGB) 3 (HMGB3.) NSCLC and adjacent tissues were collected. Reverse transcription quantitative PCR (RT-qPCR) was employed to detect expression of miR-758 and HMGB3 in NSCLC and adjacent tissues, in BEAS-2B cells and NSCLC cell lines. The targetted relationship between miR-758 and HMGB3 was identified by dual luciferase reporter gene assay. The effects of miR-758 on proliferation, migration, invasion, cell cycle, and apoptosis of A549 cells. MiR-758 expression was lower in NSCLC tissues, which was opposite to HMGB3 expression. The results also demonstrated that miR-758 can target HMGB3. The cells transfected with miR-758 mimic had decreased HMGB3 expression, proliferation, migration, and invasion, with more arrested cells in G1 phase and increased apoptosis. Our results supported that the overexpression of miR-758 inhibits proliferation, migration, and invasion, and promotes apoptosis of NSCLC cells by negative regulating HMGB2. The present study may provide a novel target for NSCLC treatment.
Zhou GH
，Lu YY
，Xie JL
，Gao ZK
，Wu XB
，Yao WS
，Gu WG
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CIRP promotes the progression of non-small cell lung cancer through activation of Wnt/β-catenin signaling via CTNNB1.
Cold-inducible RNA binding protein (CIRP) is a newly discovered proto-oncogene. In this study, we investigated the role of CIRP in the progression of non-small cell lung cancer (NSCLC) using patient tissue samples, cultured cell lines and animal lung cancer models.
Tissue arrays, IHC and HE staining, immunoblotting, and qRT-PCR were used to detect the indicated gene expression; plasmid and siRNA transfections as well as viral infection were used to manipulate gene expression; cell proliferation assay, cell cycle analysis, cell migration and invasion analysis, soft agar colony formation assay, tail intravenous injection and subcutaneous inoculation of animal models were performed to study the role of CIRP in NSCLC cells; Gene expression microarray was used to select the underlying pathways; and RNA immunoprecipitation assay, biotin pull-down assay, immunopurification assay, mRNA decay analyses and luciferase reporter assay were performed to elucidate the mechanisms. The log-rank (Mantel-Cox) test, independent sample T-test, nonparametric Mann-Whitney test, Spearman rank test and two-tailed independent sample T-test were used accordingly in our study.
Our data showed that CIRP was highly expressed in NSCLC tissue, and its level was negatively correlated with the prognosis of NSCLC patients. By manipulating CIRP expression in A549, H460, H1299, and H1650 cell lines, we demonstrated that CIRP overexpression promoted the transition of G1/G0 phase to S phase and the formation of an enhanced malignant phenotype of NSCLC, reflected by increased proliferation, enhanced invasion/metastasis and greater tumorigenic capabilities both in vitro and in vivo. Transcriptome sequencing further demonstrated that CIRP acted on the cell cycle, DNA replication and Wnt signaling pathway to exert its pro-oncogenic action. Mechanistically, CIRP directly bound to the 3'- and 5'-UTRs of CTNNB1 mRNA, leading to enhanced stability and translation of CTNNB1 mRNA and promoting IRES-mediated protein synthesis, respectively. Eventually, the increased CTNNB1 protein levels mediated excessive activation of the Wnt/β-catenin signaling pathway and its downstream targets C-myc, COX-2, CCND1, MMP7, VEGFA and CD44.
Our results support CIRP as a candidate oncogene in NSCLC and a potential target for NSCLC therapy.
Liao Y
，Feng J
，Sun W
，Wu C
，Li J
，Jing T
，Liang Y
，Qian Y
，Liu W
，Wang H
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《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》
Downregulation of microRNA-532-5p promotes the proliferation and invasion of bladder cancer cells through promotion of HMGB3/Wnt/β-catenin signaling.
Accumulating evidence has shown that altered expression of microRNA-532-5p (miR-532-5p) is involved in the development and progression of various cancers. However, little is known about the role of miR-532-5p in bladder cancer. In this study, we aimed to investigate the expression, biological function, and regulatory mechanism of miR-532-5p in bladder cancer. Herein, we found that miR-532-5p expression was frequently downregulated in bladder cancer tissues and cell lines compared with normal controls. Functional experiments showed that overexpression of miR-532-5p inhibited the proliferation and invasion of bladder cancer cells, whereas inhibition of miR-532-5p showed opposite effects. Interestingly, bioinformatics analysis predicted high-mobility group protein B3 (HMGB3) as a potential target gene of miR-532-5p. Further experiments showed that miR-532-5p directly targeted the 3'-UTR of HMGB3 and negatively regulated its expression in bladder cancer cells. Moreover, HMGB3 expression was upregulated in bladder cancer tissues and showed inverse correlation with miR-532-5p expression. Notably, miR-532-5p regulated the nuclear expression of β-catenin and activation of Wnt/β-catenin signaling in bladder cancer cells. However, restoration of HMGB3 expression partially reversed the antitumor effect of miR-532-5p overexpression, while knockdown of HMGB3 partially abrogated the oncogenic effect of miR-532-5p inhibition. Taken together, our results demonstrated that miR-532-5p inhibited the proliferation and invasion of bladder cancer cells by targeting HMGB3 and downregulating Wnt/β-catenin signaling, suggesting a tumor suppressive role of miR-532-5p in bladder cancer. Our study highlights an importance of the miR-532-5p/HMGB3 axis in bladder cancer and suggests that targeting miR-532-5p/HMGB3 may have potential applications for development of bladder cancer therapy.
Xie X
，Pan J
，Han X
，Chen W
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