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Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway.

Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, Chen J, Liu X, Wang SK - Oncotarget (2015)

Bottom Line: The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers.Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC.Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT
The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers. However, the biological role and clinical significance of UCA1 in the carcinogenesis of hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival. UCA1 depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Furthermore, UCA1 could act as an endogenous sponge by directly binding to miR-216b and downregulation miR-216b expression. In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway. Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC. Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.

No MeSH data available.


Related in: MedlinePlus

UCA1 reverses the inhibitory effect of miR-216b on cell growth and metastasis of HCC cells in vitro and in vivo(A) Cell growth viability was assayed in miR-NC, miR-216b transfected or miR-216b + pcDNA-NC or miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells by CCK-8. (B) Representative results of colony formation assay after SMMC7721 cells were transfected with miR-NC, miR-216b or co-transfected with miR-216b + pcDNA/UCA1 vectors. (C) Cell cycle profile was examined in miR-NC, miR-216b transfected or miR-216b and pcDNA/UCA1 co-transfected HepG2 cells by flow cytometry. Transwell assays were performed to investigate changes in SMMC7721 cell migration (D) and HepG2 cell invasiveness (E). Cells were treated with miR-NC, miR-216b or miR-216b + pcDNA/UCA1 vectors. The number of migrated and invaded cells was measured in the right panel, respectively. (F) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with miR-216b or co-transfected with miR-216b and pcDNA/UCA1 vectors. The tumor volume was calculated every 7 days from 2 to 6 weeks. (G) Photographs of tumor xenografts 6 weeks after inoculation. All experiments were at least repeated in triplicate, mean ± SD, *P < 0.05, **P < 0.01.
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Figure 5: UCA1 reverses the inhibitory effect of miR-216b on cell growth and metastasis of HCC cells in vitro and in vivo(A) Cell growth viability was assayed in miR-NC, miR-216b transfected or miR-216b + pcDNA-NC or miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells by CCK-8. (B) Representative results of colony formation assay after SMMC7721 cells were transfected with miR-NC, miR-216b or co-transfected with miR-216b + pcDNA/UCA1 vectors. (C) Cell cycle profile was examined in miR-NC, miR-216b transfected or miR-216b and pcDNA/UCA1 co-transfected HepG2 cells by flow cytometry. Transwell assays were performed to investigate changes in SMMC7721 cell migration (D) and HepG2 cell invasiveness (E). Cells were treated with miR-NC, miR-216b or miR-216b + pcDNA/UCA1 vectors. The number of migrated and invaded cells was measured in the right panel, respectively. (F) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with miR-216b or co-transfected with miR-216b and pcDNA/UCA1 vectors. The tumor volume was calculated every 7 days from 2 to 6 weeks. (G) Photographs of tumor xenografts 6 weeks after inoculation. All experiments were at least repeated in triplicate, mean ± SD, *P < 0.05, **P < 0.01.

Mentions: In view of the inhibitory effect of UCA1 on miR-216b expression in HCC, we further investigated whether UCA1 had the same effect on the function of miR-216b. Compared with miR-NC treatment groups, miR-216b significantly reduced cell viability in both at 48 and 72 h after transfection into SMMC7721 and HepG2 cells. However, compared with miR-216b or miR-216b + pcDNA-NC treatment groups, the cell viability in miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells was obviously increased and could basically restore to the original growth activity (Figure 5A). In colony formation assays, the colony numbers of SMMC7721 cells transfected with miR-216b were significantly less than those of miR-NC treated cells. Interestingly, the colony numbers in miR-216b and pcDNA/UCA1 co-transfected SMMC7721 cells were drastically increased than those of miR-216b treated cells, which showed the similar results with those of CCK-8 assay (Figure 5B). The examination of cell cycle profile showed that G0/G1 cell cycle arrest was induced in miR-216b transfected HepG2 cells, inversely, less G0/G1 phase and more S+G2/M phase cells were observed after HepG2 cells were co-transfected with miR-216b and pcDNA/UCA1 vectors (Figure 5C). Our data shows that miR-216b, acting as a tumor suppressor gene, inhibits cell proliferation, colony formation and induces G0/G1 cell cycle arrest, whereas, UCA1 can overturn these inhibitory effects of miR-216b on HCC cells.


Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway.

Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, Chen J, Liu X, Wang SK - Oncotarget (2015)

UCA1 reverses the inhibitory effect of miR-216b on cell growth and metastasis of HCC cells in vitro and in vivo(A) Cell growth viability was assayed in miR-NC, miR-216b transfected or miR-216b + pcDNA-NC or miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells by CCK-8. (B) Representative results of colony formation assay after SMMC7721 cells were transfected with miR-NC, miR-216b or co-transfected with miR-216b + pcDNA/UCA1 vectors. (C) Cell cycle profile was examined in miR-NC, miR-216b transfected or miR-216b and pcDNA/UCA1 co-transfected HepG2 cells by flow cytometry. Transwell assays were performed to investigate changes in SMMC7721 cell migration (D) and HepG2 cell invasiveness (E). Cells were treated with miR-NC, miR-216b or miR-216b + pcDNA/UCA1 vectors. The number of migrated and invaded cells was measured in the right panel, respectively. (F) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with miR-216b or co-transfected with miR-216b and pcDNA/UCA1 vectors. The tumor volume was calculated every 7 days from 2 to 6 weeks. (G) Photographs of tumor xenografts 6 weeks after inoculation. All experiments were at least repeated in triplicate, mean ± SD, *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 5: UCA1 reverses the inhibitory effect of miR-216b on cell growth and metastasis of HCC cells in vitro and in vivo(A) Cell growth viability was assayed in miR-NC, miR-216b transfected or miR-216b + pcDNA-NC or miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells by CCK-8. (B) Representative results of colony formation assay after SMMC7721 cells were transfected with miR-NC, miR-216b or co-transfected with miR-216b + pcDNA/UCA1 vectors. (C) Cell cycle profile was examined in miR-NC, miR-216b transfected or miR-216b and pcDNA/UCA1 co-transfected HepG2 cells by flow cytometry. Transwell assays were performed to investigate changes in SMMC7721 cell migration (D) and HepG2 cell invasiveness (E). Cells were treated with miR-NC, miR-216b or miR-216b + pcDNA/UCA1 vectors. The number of migrated and invaded cells was measured in the right panel, respectively. (F) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with miR-216b or co-transfected with miR-216b and pcDNA/UCA1 vectors. The tumor volume was calculated every 7 days from 2 to 6 weeks. (G) Photographs of tumor xenografts 6 weeks after inoculation. All experiments were at least repeated in triplicate, mean ± SD, *P < 0.05, **P < 0.01.
Mentions: In view of the inhibitory effect of UCA1 on miR-216b expression in HCC, we further investigated whether UCA1 had the same effect on the function of miR-216b. Compared with miR-NC treatment groups, miR-216b significantly reduced cell viability in both at 48 and 72 h after transfection into SMMC7721 and HepG2 cells. However, compared with miR-216b or miR-216b + pcDNA-NC treatment groups, the cell viability in miR-216b + pcDNA/UCA1 co-transfected SMMC7721 and HepG2 cells was obviously increased and could basically restore to the original growth activity (Figure 5A). In colony formation assays, the colony numbers of SMMC7721 cells transfected with miR-216b were significantly less than those of miR-NC treated cells. Interestingly, the colony numbers in miR-216b and pcDNA/UCA1 co-transfected SMMC7721 cells were drastically increased than those of miR-216b treated cells, which showed the similar results with those of CCK-8 assay (Figure 5B). The examination of cell cycle profile showed that G0/G1 cell cycle arrest was induced in miR-216b transfected HepG2 cells, inversely, less G0/G1 phase and more S+G2/M phase cells were observed after HepG2 cells were co-transfected with miR-216b and pcDNA/UCA1 vectors (Figure 5C). Our data shows that miR-216b, acting as a tumor suppressor gene, inhibits cell proliferation, colony formation and induces G0/G1 cell cycle arrest, whereas, UCA1 can overturn these inhibitory effects of miR-216b on HCC cells.

Bottom Line: The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers.Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC.Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.

View Article: PubMed Central - PubMed

Affiliation: Central Laboratory, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.

ABSTRACT
The long non-coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) has been recently shown to be dysregulated, which plays an important role in the progression of several cancers. However, the biological role and clinical significance of UCA1 in the carcinogenesis of hepatocellular carcinoma (HCC) remain unclear. Herein, we found that UCA1 was aberrantly upregulated in HCC tissues and associated with TNM stage, metastasis and postoperative survival. UCA1 depletion inhibited the growth and metastasis of HCC cell lines in vitro and in vivo. Furthermore, UCA1 could act as an endogenous sponge by directly binding to miR-216b and downregulation miR-216b expression. In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway. Taken together, our data highlights the pivotal role of UCA1 in the tumorigenesis of HCC. Moreover, the present study elucidates a novel lncRNA-miRNA-mRNA regulatory network that is UCA1-miR-216b-FGFR1-ERK signaling pathway in HCC, which may help to lead a better understanding the pathogenesis of HCC and probe the feasibility of lncRNA-directed diagnosis and therapy for this deadly disease.

No MeSH data available.


Related in: MedlinePlus