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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 exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.(a). Huh7 cells were infected with lentiviruses expressing scrambled or Pin1 shRNA. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated. (b). Huh7 cells were infected with lentiviruses expressing miR-NC, miR-140-5p or miR-140-5p combined with overexpression of Flag-Pin1. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated.
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f3: MiR-140-5p exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.(a). Huh7 cells were infected with lentiviruses expressing scrambled or Pin1 shRNA. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated. (b). Huh7 cells were infected with lentiviruses expressing miR-NC, miR-140-5p or miR-140-5p combined with overexpression of Flag-Pin1. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated.

Mentions: We and others have shown that Pin1 regulates multiple cancer pathways28. To further support the notion that miR-140-5p exerts potent anticancer activity against HCC by targeting Pin1, we examined the effects of miR-140-5p on a set of oncoproteins, which are substrates for Pin1 and whose protein stability is maintained by Pin1, with Pin1 knockdown as a positive control. Like Pin1 knockdown (Fig. 3a), moderate overexpression of miR-140-5p caused a significant decrease in the abundance of Pin1 and its downstream oncoproteins, including cyclin D151, CDK252, AKT53, pAKt-47352, ERK28, pERK2854, and NF-κB p6548 (Fig. 3b). Moreover, these effects were partially rescued by reconstitution of miR-140-5p-resistant Pin1 (Fig. 3b). Thus, miR-140-5p exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.


MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways
MiR-140-5p exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.(a). Huh7 cells were infected with lentiviruses expressing scrambled or Pin1 shRNA. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated. (b). Huh7 cells were infected with lentiviruses expressing miR-NC, miR-140-5p or miR-140-5p combined with overexpression of Flag-Pin1. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: MiR-140-5p exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.(a). Huh7 cells were infected with lentiviruses expressing scrambled or Pin1 shRNA. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated. (b). Huh7 cells were infected with lentiviruses expressing miR-NC, miR-140-5p or miR-140-5p combined with overexpression of Flag-Pin1. Cell lysates were subjected to Western blot analysis with antibodies against various proteins indicated.
Mentions: We and others have shown that Pin1 regulates multiple cancer pathways28. To further support the notion that miR-140-5p exerts potent anticancer activity against HCC by targeting Pin1, we examined the effects of miR-140-5p on a set of oncoproteins, which are substrates for Pin1 and whose protein stability is maintained by Pin1, with Pin1 knockdown as a positive control. Like Pin1 knockdown (Fig. 3a), moderate overexpression of miR-140-5p caused a significant decrease in the abundance of Pin1 and its downstream oncoproteins, including cyclin D151, CDK252, AKT53, pAKt-47352, ERK28, pERK2854, and NF-κB p6548 (Fig. 3b). Moreover, these effects were partially rescued by reconstitution of miR-140-5p-resistant Pin1 (Fig. 3b). Thus, miR-140-5p exerts potent anticancer activity against HCC by ablating Pin1 and thereby blocking multiple cancer pathways simultaneously.

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