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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 depletion inhibits tumor growth in vivo(A) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with siRNA-NC or siUCA1. The tumor volume was calculated every 7 days from 2 to 6 weeks. (B) Photographs of representative tumor formation in nude mice and tumor xenografts 6 weeks after inoculation. (C) qRT-PCR analysis of UCA1 expression in tissues of resected tumors formed from siUCA1 or siRNA-NC transfencted SMMC7721 cells. (D) Tumors developed from siUCA1 transfected cells showed a lower level of PCNA protein expression than tumors developed from siRNA-NC transfected cells. Upper: H&E staining; Lower: immunostaining (×200). Quantification of immunohistochemical assay was represented as percentage of PCNA positively-stained cells from 5 arbitrarily selected fields, mean ± SD, **P < 0.01.
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Figure 3: UCA1 depletion inhibits tumor growth in vivo(A) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with siRNA-NC or siUCA1. The tumor volume was calculated every 7 days from 2 to 6 weeks. (B) Photographs of representative tumor formation in nude mice and tumor xenografts 6 weeks after inoculation. (C) qRT-PCR analysis of UCA1 expression in tissues of resected tumors formed from siUCA1 or siRNA-NC transfencted SMMC7721 cells. (D) Tumors developed from siUCA1 transfected cells showed a lower level of PCNA protein expression than tumors developed from siRNA-NC transfected cells. Upper: H&E staining; Lower: immunostaining (×200). Quantification of immunohistochemical assay was represented as percentage of PCNA positively-stained cells from 5 arbitrarily selected fields, mean ± SD, **P < 0.01.

Mentions: To assess the effects of siUCA1 on the in vivo growth of HCC cells, we applied a xenograft model in which the SMCC7721 cells treated with siUCA1 or siRNA-NC were subcutaneously injected into the flanks of athymic mice and were allowed to develop measurable tumors. There was no animal death in the course of the treatment and no other complications such as skin necrosis were detected due to infection. The tumor formation rate in siRNA-NC transfected group was 90% (9/10); whereas only 60% (6/10) nude mice in siUCA1 transfected group gave rise to tumors. During the whole tumor growth period, tumors from the siUCA1 transfected SMMC7721 cells grew slower than that of siRNA-NC transfected ones (Figure 3A). After 6-week inoculation, the average weight of tumors developed from siUCA1 transfected SMMC7721 cells (217 ± 17 mg) was obviously smaller than those of control mice (592 ± 32 mg) (Figure 3B). Next, qRT-PCR analysis of UCA1 expression and immunostaining analysis of proliferating cell nuclear antigen (PCNA) protein expression were performed in resected tumor tissues. As shown in Figure 3C, the level of UCA1 expression in tumors formed from siUCA1 transfected SMMC7721 cells was significantly lower than that in tumors formed from control cells. In comparison with that in tumors formed from control cells, the positive rate of PCNA expression in tumors developed from siUCA1 transfected SMMC7721 cells was significantly decreased (Figure 3D). These results suggest that UCA1 depletion can inhibit proliferation capacity of HCC cells in vivo.


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 depletion inhibits tumor growth in vivo(A) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with siRNA-NC or siUCA1. The tumor volume was calculated every 7 days from 2 to 6 weeks. (B) Photographs of representative tumor formation in nude mice and tumor xenografts 6 weeks after inoculation. (C) qRT-PCR analysis of UCA1 expression in tissues of resected tumors formed from siUCA1 or siRNA-NC transfencted SMMC7721 cells. (D) Tumors developed from siUCA1 transfected cells showed a lower level of PCNA protein expression than tumors developed from siRNA-NC transfected cells. Upper: H&E staining; Lower: immunostaining (×200). Quantification of immunohistochemical assay was represented as percentage of PCNA positively-stained cells from 5 arbitrarily selected fields, mean ± SD, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480724&req=5

Figure 3: UCA1 depletion inhibits tumor growth in vivo(A) Tumor growth curves measured after injection of SMMC7721 cells stably transfected with siRNA-NC or siUCA1. The tumor volume was calculated every 7 days from 2 to 6 weeks. (B) Photographs of representative tumor formation in nude mice and tumor xenografts 6 weeks after inoculation. (C) qRT-PCR analysis of UCA1 expression in tissues of resected tumors formed from siUCA1 or siRNA-NC transfencted SMMC7721 cells. (D) Tumors developed from siUCA1 transfected cells showed a lower level of PCNA protein expression than tumors developed from siRNA-NC transfected cells. Upper: H&E staining; Lower: immunostaining (×200). Quantification of immunohistochemical assay was represented as percentage of PCNA positively-stained cells from 5 arbitrarily selected fields, mean ± SD, **P < 0.01.
Mentions: To assess the effects of siUCA1 on the in vivo growth of HCC cells, we applied a xenograft model in which the SMCC7721 cells treated with siUCA1 or siRNA-NC were subcutaneously injected into the flanks of athymic mice and were allowed to develop measurable tumors. There was no animal death in the course of the treatment and no other complications such as skin necrosis were detected due to infection. The tumor formation rate in siRNA-NC transfected group was 90% (9/10); whereas only 60% (6/10) nude mice in siUCA1 transfected group gave rise to tumors. During the whole tumor growth period, tumors from the siUCA1 transfected SMMC7721 cells grew slower than that of siRNA-NC transfected ones (Figure 3A). After 6-week inoculation, the average weight of tumors developed from siUCA1 transfected SMMC7721 cells (217 ± 17 mg) was obviously smaller than those of control mice (592 ± 32 mg) (Figure 3B). Next, qRT-PCR analysis of UCA1 expression and immunostaining analysis of proliferating cell nuclear antigen (PCNA) protein expression were performed in resected tumor tissues. As shown in Figure 3C, the level of UCA1 expression in tumors formed from siUCA1 transfected SMMC7721 cells was significantly lower than that in tumors formed from control cells. In comparison with that in tumors formed from control cells, the positive rate of PCNA expression in tumors developed from siUCA1 transfected SMMC7721 cells was significantly decreased (Figure 3D). These results suggest that UCA1 depletion can inhibit proliferation capacity of HCC cells in vivo.

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