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MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways

View Article: PubMed Central - PubMed

ABSTRACT

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related-death. As a major common regulator of numerous cancer-driving pathways and a unique therapeutic target, the prolyl isomerase Pin1 is overexpressed in a majority of HCCs, whereas the mechanism underlying Pin1 overexpression remains elusive. Here we find that miR-140-5p inhibits HCC by directly targeting Pin1 to block multiple cancer-driving pathways. Bioinformatics analysis, miRNA binding and functional assays identify that miR-140-5p directly interacts with the 3′UTR of Pin1 and inhibits Pin1 translation. Furthermore, like stable Pin1 knockdown, moderate overexpression of miR-140-5p not only eliminates Pin1, but also inhibits cells growth and metastasis. Importantly, these effects of miR-140-5p are largely rescued by reconstitution of Pin1. Moreover, miR-140-5p inhibits multiple Pin1-dependent cancer pathways and suppresses tumor growth in mice. The clinical significance of these findings has been substantiated by the demonstrations that miR-140-5p is frequently down-regulated and inversely correlated with Pin1 overexpression in HCC tissues and cell lines. Given prevalent miR-140-5p downregulation in other cancers and major impact of Pin1 overexpression on activating numerous cancer-driving pathways including global miRNA downregulation, the miR-140-5p/Pin1 axis may play a major role in tumorigenesis and offer promising therapeutic targets for HCC and other cancers.

No MeSH data available.


Related in: MedlinePlus

MiR-140-5p inhibits HCC tumor growth by targeting Pin1 in vivo.Mice were xenografted with Huh7 cells stably infected with NC or miR-140-5p lentivirus on either side of the flanks of the same mice. (a). Huh7 tumor volumes were measured semiweekly for 8 weeks and the curves of tumor volumes were plotted over time. (b). Photographic illustration of tumors harvested from nude mice at the end point (8 weeks). Each scale of the ruler represents 1 mm. (c). Weights of tumors in these two groups were calculated and compared. Error bar represents SEM (n = 10). (d). Representative immunoblots of Pin1 and cyclin D1 expression in xenograft tumors from nude mice, along with actin as a loading control.
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f4: MiR-140-5p inhibits HCC tumor growth by targeting Pin1 in vivo.Mice were xenografted with Huh7 cells stably infected with NC or miR-140-5p lentivirus on either side of the flanks of the same mice. (a). Huh7 tumor volumes were measured semiweekly for 8 weeks and the curves of tumor volumes were plotted over time. (b). Photographic illustration of tumors harvested from nude mice at the end point (8 weeks). Each scale of the ruler represents 1 mm. (c). Weights of tumors in these two groups were calculated and compared. Error bar represents SEM (n = 10). (d). Representative immunoblots of Pin1 and cyclin D1 expression in xenograft tumors from nude mice, along with actin as a loading control.

Mentions: To demonstrate that miR-140-5p could inhibit HCC tumor growth by targeting Pin1 in vivo, we subcutaneously injected stable miR-140-5p- or miR-NC (negative control)-expressing Huh7 cells into the either flank of the same nude mice, followed by monitoring tumor growth for 8 weeks after implantation. The size of subcutaneous tumors originated from miR-140-5p-transduced Huh7 cells was dramatically smaller than that of miR-NC (negative control)-transduced cells, as revealed by tumor growth curves, photographic illustration of final tumors or their weights (Fig. 4a,b and c). Moreover, miR-140-5p significantly decreased the abundance of Pin1 and its functional readout cyclin D1 in tumors as compared to controls (Fig. 4d), consistent with the above in vitro results (Figs 1f and 3c). Taken together, our data show that miR-140-5p has potent anti-tumor activity against HCC through targeting Pin1 to block multiple cancer pathways in vitro and in vivo.


MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways
MiR-140-5p inhibits HCC tumor growth by targeting Pin1 in vivo.Mice were xenografted with Huh7 cells stably infected with NC or miR-140-5p lentivirus on either side of the flanks of the same mice. (a). Huh7 tumor volumes were measured semiweekly for 8 weeks and the curves of tumor volumes were plotted over time. (b). Photographic illustration of tumors harvested from nude mice at the end point (8 weeks). Each scale of the ruler represents 1 mm. (c). Weights of tumors in these two groups were calculated and compared. Error bar represents SEM (n = 10). (d). Representative immunoblots of Pin1 and cyclin D1 expression in xenograft tumors from nude mice, along with actin as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382892&req=5

f4: MiR-140-5p inhibits HCC tumor growth by targeting Pin1 in vivo.Mice were xenografted with Huh7 cells stably infected with NC or miR-140-5p lentivirus on either side of the flanks of the same mice. (a). Huh7 tumor volumes were measured semiweekly for 8 weeks and the curves of tumor volumes were plotted over time. (b). Photographic illustration of tumors harvested from nude mice at the end point (8 weeks). Each scale of the ruler represents 1 mm. (c). Weights of tumors in these two groups were calculated and compared. Error bar represents SEM (n = 10). (d). Representative immunoblots of Pin1 and cyclin D1 expression in xenograft tumors from nude mice, along with actin as a loading control.
Mentions: To demonstrate that miR-140-5p could inhibit HCC tumor growth by targeting Pin1 in vivo, we subcutaneously injected stable miR-140-5p- or miR-NC (negative control)-expressing Huh7 cells into the either flank of the same nude mice, followed by monitoring tumor growth for 8 weeks after implantation. The size of subcutaneous tumors originated from miR-140-5p-transduced Huh7 cells was dramatically smaller than that of miR-NC (negative control)-transduced cells, as revealed by tumor growth curves, photographic illustration of final tumors or their weights (Fig. 4a,b and c). Moreover, miR-140-5p significantly decreased the abundance of Pin1 and its functional readout cyclin D1 in tumors as compared to controls (Fig. 4d), consistent with the above in vitro results (Figs 1f and 3c). Taken together, our data show that miR-140-5p has potent anti-tumor activity against HCC through targeting Pin1 to block multiple cancer pathways in vitro and in vivo.

View Article: PubMed Central - PubMed

ABSTRACT

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related-death. As a major common regulator of numerous cancer-driving pathways and a unique therapeutic target, the prolyl isomerase Pin1 is overexpressed in a majority of HCCs, whereas the mechanism underlying Pin1 overexpression remains elusive. Here we find that miR-140-5p inhibits HCC by directly targeting Pin1 to block multiple cancer-driving pathways. Bioinformatics analysis, miRNA binding and functional assays identify that miR-140-5p directly interacts with the 3′UTR of Pin1 and inhibits Pin1 translation. Furthermore, like stable Pin1 knockdown, moderate overexpression of miR-140-5p not only eliminates Pin1, but also inhibits cells growth and metastasis. Importantly, these effects of miR-140-5p are largely rescued by reconstitution of Pin1. Moreover, miR-140-5p inhibits multiple Pin1-dependent cancer pathways and suppresses tumor growth in mice. The clinical significance of these findings has been substantiated by the demonstrations that miR-140-5p is frequently down-regulated and inversely correlated with Pin1 overexpression in HCC tissues and cell lines. Given prevalent miR-140-5p downregulation in other cancers and major impact of Pin1 overexpression on activating numerous cancer-driving pathways including global miRNA downregulation, the miR-140-5p/Pin1 axis may play a major role in tumorigenesis and offer promising therapeutic targets for HCC and other cancers.

No MeSH data available.


Related in: MedlinePlus