miR-124-3p Suppresses the Invasiveness and Metastasis of Hepatocarcinoma Cells via Targeting CRKL

Abstract

Abnormal expressions of microRNAs are involved in growth and progression of human cancers including hepatocellular carcinoma (HCC). An adaptor protein CRKL plays a pivotal role in HCC growth, whereas miR-124-3p downregulation is associated with clinical stage and the poor survival of patients. However, the relationship between miR-124-3p and CRKL and the molecular mechanisms through which they regulate HCC metastasis remains unclear. In the current work, we explored miR-124-3p and its correlation with CRKL expression in HCC patient tissues. We found that miR-124-3p deficiency is inversely co-related with CRKL overexpression in tumorous tissues of HCC patients, which was also consistent in HCCLM3 and Huh7 HCC cell lines. Target validation data shows that miR-124-3p directly targets CRKL. The overexpression of miR-124-3p reverses the CRKL expression at both mRNA and protein levels and inhibits the cell development, migration, and invasion. Mechanistic investigations showed that CRKL downregulation suppresses the ERK pathway and EMT process, and concomitant decrease in invasion and metastasis of HCC cells. The expressions of key molecules in the ERK pathway such as RAF, MEK, ERK1/2, and pERK1/2 and key promoters of EMT such as N -cadherin and vimentin were downregulated, whereas E -cadherin, a key suppression indicator of EMT, was upregulated. MiR-124-3p-mediated CRKL suppression led to BAX/BCL-2 increase and C-JUN downregulation, which inhibited the cell proliferation and promoted the apoptosis in HCC cells. Collectively, our data illustrates that miR-124-3p acts as an important tumor-suppressive miRNA to suppress HCC carcinogenesis through targeting CRKL. The miR-124-3p-CRKL axial regulated pathway may offer valuable indications for cancer research, diagnosis, and treatment.

Upregulating microRNA-373-3p promotes apoptosis and inhibits metastasis of hepatocellular carcinoma cells

“…miR-631 targets PTPRE to dampen HCC migration, invasion, EMT, and intrahepatic metastasis [ 34 ]. Similar effects on liver cancer are also reflected in the other miRNAs like miR-199a-3p [ 35 ], miR-124-3p [ 36 ], and miR-216a-3p [ 37 ]. miR-373-3p is a novel miRNA first uncovered by Syring et al Its expression is substantially heightened in the serum of patients suffering from testicular germ cell tumors [ 38 ].…”

MiR-4521 plays a tumor repressive role in growth and metastasis of hepatocarcinoma cells by suppressing phosphorylation of FAK/AKT pathway via targeting FAM129A

“…Deregulation of microRNAs has been confirmed in nearly all kinds of human cancers [30] , together with renal cancer [11] , glioma [31] , colon cancer [32] , ovarian cancer [33] , hepatocellular carcinoma [8] and bladder cancer [34] . miRNAs are generally involved in tumorigenesis via regulatory genes and signaling pathways [35] .…”

“…Although microRNAs have no coding potential, they are molecules of interest as they are able to regulate many biological mechanisms, including cell pathogenesis [7] . MicroRNAs are reported to be involved in various biological cell functions including proliferation, apoptosis, metastasis and differentiation [8] , [9] . They act as post transcriptional controllers by inhibiting the translation or by breaking mRNA into fragments [10] .…”

Changes in Methylation across Structural and MicroRNA Genes Relevant for Progression and Metastasis in Colorectal Cancer

“…Many of these miRs we found significantly differentially methylated in CRC also already have been shown to take functional roles in diverse further cancer entities besides CRC, which were in part related to changes in the methylation of their genes. For example, a tumor-suppressor function has been ascribed to all three loci encoding mature hsa-miR-124 (hsa-miR-124-1/-2/-3), which has been shown to be hypermethylated in cervical tumors [ 30 ], prostate cancer [ 31 ], nasopharyngeal carcinoma [ 85 ], HCC [ 32 , 33 ], bladder cancer [ 34 ], and CRC [ 35 , 36 , 37 ]. Likewise, mature miR-129-2 miR has been shown to be a tumor suppressor in esophageal cancer [ 38 ], breast cancer [ 39 ], and CRC [ 40 ].…”