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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 promotes HCC malignant progression through ERK signaling pathwayRepresentative western blotting results for ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 protein expression from siRNA-NC or siUCA1 treated HepG2 cells (A) and pcDNA-NC or pcDNA/UCA1 treated SMMC7721 cells (B) (upper panel). (C) Representative western blotting results for ERK1/2 and p-ERK1/2 protein expression from pcDNA/UCA1 + si-NC or pcDNA/UCA1 + si-FGFR1 treated HepG2 and SMMC7721 cells. The relative protein expression levels were obtained from three independent experiments, β-actin was used as a control, mean ± SD, **P < 0.01, (lower panel). (D) Diagram depicting the regulation mechanism of UCA1 in the tumorigenesis of HCC.
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Figure 7: UCA1 promotes HCC malignant progression through ERK signaling pathwayRepresentative western blotting results for ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 protein expression from siRNA-NC or siUCA1 treated HepG2 cells (A) and pcDNA-NC or pcDNA/UCA1 treated SMMC7721 cells (B) (upper panel). (C) Representative western blotting results for ERK1/2 and p-ERK1/2 protein expression from pcDNA/UCA1 + si-NC or pcDNA/UCA1 + si-FGFR1 treated HepG2 and SMMC7721 cells. The relative protein expression levels were obtained from three independent experiments, β-actin was used as a control, mean ± SD, **P < 0.01, (lower panel). (D) Diagram depicting the regulation mechanism of UCA1 in the tumorigenesis of HCC.

Mentions: Documents have reported that FGFR mediates FGF signaling, playing crucial roles in cancer cell proliferation, migration, angiogenesis and survival, mainly through activation of the mitogen activated protein kinase (MAPK) signaling pathway, including extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) pathways [28, 29]. To further explore the potential mechanism that might be involved in the UCA1-associated malignant progression of HCC, we examined the protein expression levels of ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 in HCC cell lines. Western blot analysis revealed that compared with the siRNA-NC, the protein expression levels of ERK1/2 and p-ERK1/2 were markedly reduced in the siUCA1 transfected HepG2 cells. Moreover, compared with the pcDNA-NC, the protein expression levels of ERK1/2 and p-ERK1/2 were notably elevated in the pcDNA/UCA1 transfected SMMC7721 cells. However, the protein expression levels of JNK, p-JNK, p38 and p-p38 were not significantly changed in both siUCA1 treated HepG2 cells and pcDNA/UCA1 treated SMMC7721 cells (Figure 7A, 7B). In addition, compared with the pcDNA/UCA1+ si-NC co-transfected groups, the protein expression levels of ERK1/2 and p-ERK1/2 were significantly decreased in pcDNA/UCA1 and si-FGFR1 co-transfected HepG2 and SMMC7721 cells (Figure 7C). Because ERK signaling plays a central role in the carcinogenesis and maintenance of common cancers, the dysregulated expression of ERK1/2 and p-ERK1/2 also affects the expression of its potential downstream targets, which are responsible for a wide range of biological processes such as cell proliferation and differentiation, cell cycle and survival, cell migration and invasion, etc. Thus, our present results indicate that UCA1 may facilitate HCC malignant progression partly through FGFR1/ERK, rather than FGFR1/JNK or FGFR1/p38 MAPK, signaling pathway.


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 promotes HCC malignant progression through ERK signaling pathwayRepresentative western blotting results for ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 protein expression from siRNA-NC or siUCA1 treated HepG2 cells (A) and pcDNA-NC or pcDNA/UCA1 treated SMMC7721 cells (B) (upper panel). (C) Representative western blotting results for ERK1/2 and p-ERK1/2 protein expression from pcDNA/UCA1 + si-NC or pcDNA/UCA1 + si-FGFR1 treated HepG2 and SMMC7721 cells. The relative protein expression levels were obtained from three independent experiments, β-actin was used as a control, mean ± SD, **P < 0.01, (lower panel). (D) Diagram depicting the regulation mechanism of UCA1 in the tumorigenesis of HCC.
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Figure 7: UCA1 promotes HCC malignant progression through ERK signaling pathwayRepresentative western blotting results for ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 protein expression from siRNA-NC or siUCA1 treated HepG2 cells (A) and pcDNA-NC or pcDNA/UCA1 treated SMMC7721 cells (B) (upper panel). (C) Representative western blotting results for ERK1/2 and p-ERK1/2 protein expression from pcDNA/UCA1 + si-NC or pcDNA/UCA1 + si-FGFR1 treated HepG2 and SMMC7721 cells. The relative protein expression levels were obtained from three independent experiments, β-actin was used as a control, mean ± SD, **P < 0.01, (lower panel). (D) Diagram depicting the regulation mechanism of UCA1 in the tumorigenesis of HCC.
Mentions: Documents have reported that FGFR mediates FGF signaling, playing crucial roles in cancer cell proliferation, migration, angiogenesis and survival, mainly through activation of the mitogen activated protein kinase (MAPK) signaling pathway, including extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) pathways [28, 29]. To further explore the potential mechanism that might be involved in the UCA1-associated malignant progression of HCC, we examined the protein expression levels of ERK1/2, p-ERK1/2, JNK, p-JNK, p38 and p-p38 in HCC cell lines. Western blot analysis revealed that compared with the siRNA-NC, the protein expression levels of ERK1/2 and p-ERK1/2 were markedly reduced in the siUCA1 transfected HepG2 cells. Moreover, compared with the pcDNA-NC, the protein expression levels of ERK1/2 and p-ERK1/2 were notably elevated in the pcDNA/UCA1 transfected SMMC7721 cells. However, the protein expression levels of JNK, p-JNK, p38 and p-p38 were not significantly changed in both siUCA1 treated HepG2 cells and pcDNA/UCA1 treated SMMC7721 cells (Figure 7A, 7B). In addition, compared with the pcDNA/UCA1+ si-NC co-transfected groups, the protein expression levels of ERK1/2 and p-ERK1/2 were significantly decreased in pcDNA/UCA1 and si-FGFR1 co-transfected HepG2 and SMMC7721 cells (Figure 7C). Because ERK signaling plays a central role in the carcinogenesis and maintenance of common cancers, the dysregulated expression of ERK1/2 and p-ERK1/2 also affects the expression of its potential downstream targets, which are responsible for a wide range of biological processes such as cell proliferation and differentiation, cell cycle and survival, cell migration and invasion, etc. Thus, our present results indicate that UCA1 may facilitate HCC malignant progression partly through FGFR1/ERK, rather than FGFR1/JNK or FGFR1/p38 MAPK, signaling pathway.

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