microRNA-622 acts as a tumor suppressor in hepatocellular carcinoma

Abstract

microRNAs (miRNAs) are important regulators of tumor development and progression. In this study, we aimed to explore the expression and role of miR-622 in hepatocellular carcinoma (HCC). We found that miR-622 was significantly downregulated in human HCC specimens compared to adjacent noncancerous liver tissues. miR-622 downregulation was significantly associated with aggressive parameters and poor prognosis in HCC. Enforced expression of miR-622 significantly decreased the proliferation and colony formation and induced apoptosis of HCC cells. In vivo studies demonstrated that miR-622 overexpression retarded the growth of HCC xenograft tumors. Bioinformatic analysis and luciferase reporter assays revealed that miR-622 directly targeted the 3'-untranslated region (UTR) of mitogen-activated protein 4 kinase 4 (MAP4K4) mRNA. Ectopic expression of miR-622 led to a significant reduction of MAP4K4 expression in HCC cells and xenograft tumors. Overexpression of MAP4K4 partially restored cell proliferation and colony formation and reversed the induction of apoptosis in miR-622-overexpressing HCC cells. Inhibition of JNK and NF-κB signaling phenocopied the anticancer effects of miR-622 on HCC cells. Taken together, miR-622 acts as a tumor suppressor in HCC and restoration of miR-622 may provide therapeutic benefits in the treatment of HCC.

RETRACTED ARTICLE: The suppressing role of miR-622 in renal cell carcinoma progression by down-regulation of CCL18/MAPK signal pathway

“…They are broadly involved in a variety of biological functions of RCC development and progression including cell proliferation, metastasis, angiogenesis, drug resistance, metabolism and others [ 4 – 6 ]. MiR-622 plays an inhibiting role in various cancer like glioma [ 7 ], colorectal cancer [ 8 – 10 ], hepatocellular carcinoma [ 11 , 12 ], lung cancer [ 13 ], esophageal squamous cell carcinoma [ 14 ] and gastric cancer [ 15 ]. The biological functions of miR-622 in the reported cancers include cell proliferation and metastasis [ 7 – 15 ].…”

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

“…In contrast and according to our findings on miR-622-mediated KRAS suppression which reduced proliferation, the growth-suppressive effects of miR-622 on HCC cells were only minimally affected by its effect on CXCR4 expression [141]. Song et al found that miR-622 negatively regulates mitogen-activated protein 4 kinase 4 (MAP4K4) in HCC but overexpression of MAP4K4 only partially reversed the growth-suppressive effects of miR-622 on HCC cells [142]. In a recent study, the same group also demonstrated that MAP4K4 promoted the epithelial-mesenchymal transition and invasiveness of HCC cells largely via activation of the c-Jun N-terminal kinase(JNK) and the nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NF-κB) signaling [143].…”

“…MiR-622 downregulation also unreleases its target CXCR4 which mediates migration of tumor cells [141]. Further, low miR-622 expression induces de-repression of MAP4K4 promoting epithelial to mesenchymal transition (EMT) and invasiveness [142,143]. Low levels of miR-26a in tumor cells lead to increased integrin α5 expression and reduced E-cadherin expression inducing EMT [144][145][146].…”

“…Moreover, miR-622 was described as one of two most differentially expressed miRNAs between sporadic colon cancer and colon cancers with microsatellite instability [160]. Several studies suggested that miR-622 could affect proliferation, clonogenicity and migration in cancer cells by distinct pathways [142,161]. Recently, we identified wildtype KRAS as a novel therapeutic target in melanoma and showed that KRAS inhibition functions synergistically with BRAF inhibition [118].…”

Wild type Kirsten rat sarcoma is a novel microRNA-622-regulated therapeutic target for hepatocellular carcinoma and contributes to sorafenib resistance

“…In contrast, growth-suppressive effects of miR-622 on HCC cells were only slightly affected by its effect on CXCR4 expression 32. Song et al found that miR-622 negatively regulates mitogen-activated protein 4 kinase 4 (MAP4K4) in HCC, but overexpression of MAP4K4 only partially reversed the growth-suppressive effects of miR-622 on HCC cells 31. In a recent study, the same group demonstrated that MAP4K4 promotes the epithelial–mesenchymal transition and invasiveness of HCC cells largely via activation of c-Jun N-terminal kinases and nuclear factor kappa-light-chain-enhancer of activated B cells signalling 43.…”