research target：miR-149，hepatocellular carcinoma
Periodicals：Oncotarget
IF：5.168
Cooperative Unit:Army Medical University，UCSF School of Medicine
Time of publication：October，2015
Summary
microRNAs have been implicated in hepatocellular carcinoma (HCC) metastasis, which is predominant cause of high mortality in these patients. Although an increasing body of evidence indicates that miR-149 plays an important role in the growth and metastasis of multiple types of cancers, its role in the progression of HCC remains unknown. Here, we demonstrated that miR-149 was significantly down-regulated in HCC, which was correlated with distant metastasis and TNM stage with statistical significance. A survival analysis showed that decreased miR-149 expression was correlated with a poor prognosis of HCC as well. We found that over-expression of miR-149 suppressed migration and invasion of HCC cells in vitro. In addition, we identified PPM1F (protein phosphatase, Mg2+/Mn2+-dependent, 1F) as a direct target of miR-149 whose expression was negatively correlated with the expression of miR-149 in HCC tissues. The re-expression of PPM1F rescued the miR-149-mediated inhibition of cell migration and invasion. miR-149 regulated formation of stress fibers to inhibit migration, and re-expression of PPM1F reverted the miR-149-mediated loss of stress fibers. Moreover, we demonstrated that over-expression of miR-149 reduced pMLC2, a downstream effector of PPM1F, in MHCC-97H cells. In vivo studies confirm inhibition of HCC metastasis by miR-149. Taken together, our findings indicates that miR-149 is a potential prognostic biomarker of HCC and that the miR-149/PPM1F regulatory axis represents a novel therapeutic target for HCC treatment.
Keywords: hepatocellular carcinoma, miR-149, metastasis, PPM1F, microRNA
Research Background
Many reports have shown that the deregulation of miRNAs is involved in the growth and metastasis of HCC. For example, upregulation of miR-182 is related to intrahepatic metastasis and poor prognosis, whereas a decrease in miR-124 is significantly associated with a more aggressive phenotype and poor prognosis. miR-149 primarily functions as an anti-tumor miRNA, and its expression is deregulated in multiple types of cancers, including breast cancer , colorectal cancer (CRC), gastric cancer ,head and neck squamous cell carcinoma (HNSCC) and non-small-cell lung cancer (NSCLC) .
In this study, we demonstrate that miR-149 is frequently down-regulated and significantly correlates with tumor metastasis and poor prognosis in HCC patients. We further proved that miR-149 inhibited the metastasis of HCC in vivo and in vitro by suppressing actin-regulatory proteins PPM1F.
Partial results of cooperation
Figure 1: miR-149 is frequently down-regulated in human HCC tissue and associated with poor clinicopathologic features and a low postoperative survival rate.
Figure 2: Exogenetic over-expression of miR-149 suppresses HCC cell migration and invasion in vitro.
Figure 3: miR-149 down-regulates PPM1F expression by directly targeting its 3′-UTR.
Figure 4: PPM1F is frequently up-regulated and inversely associated with the expression of miR-149 in HCC.
Figure 5: PPM1F rescued the effect of miR-149 on the invasion and migration of HCC cells.
Figure 6: miR-149 suppresses HCC metastasis in vivo.
References
Gang L, Ya-Ling C, Bo T, et al. miR-149 represses metastasis of hepatocellular carcinoma by targeting actin-regulatory proteins PPM1F[J].
Oncotarget, 2015, 6(35):37808-23.
BersinbioTM cooperative technology：FISH
Original link：http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4741967&blobtype=pdf
