LMO3 promotes hepatocellular carcinoma invasion, metastasis and anoikis inhibition by directly interacting with LATS1 and suppressing Hippo signaling

Abstract

BackgroundIn this research, we aimed to investigate the biological functions of LIM domain only 3 (LMO3) in hepatocellular carcinoma (HCC) and uncover the underlying molecular mechanism in it.MethodsHCC tissue microarray (n = 180) was used to analyze the correlation between LMO3 expression and clinicopathological findings. In vitro transwell matrigel invasion assay and annexin V anoikis assay in HCC cells were conducted to investigate LMO3 related biological functions. In vivo intrahepatic and lung metastasis models were used to determine the role of LMO3 in HCC metastasis. Quantitative real-time PCR, western blotting and immunohistochemical staining were performed to investigate the expression and mechanism of LMO3 in HCC.ResultsWe found that the expression of LMO3 was significantly upregulated in HCC tissues, and it was closely related to clinicopathological findings and patient prognoses. Knockdown of LMO3 suppressed the invasion and anoikis inhibition of HCC cells in vitro. Meanwhile, the metastasis of SMMC-7721 cells was also suppressed by LMO3 knockdown in vivo. Furthermore, we found that LMO3 knockdown increased the phosphorylation of YAP and LATS1, and decrease Rho GTPases activities. LMO3 directly interacted with LATS1, and thus suppressed Hippo signaling. Recombinant LMO3 (rLMO3) protein administration decreased the phosphorylation of YAP and LATS1, and increased Rho GTPases activities. The inhibitors of the Hippo pathway abrogated rLMO3 protein-induced HCC cell invasion and anoikis inhibition.ConclusionsThese results suggest that LMO3 promotes HCC cell invasion and anoikis inhibition by interacting with LATS1 and suppressing Hippo signaling. LMO3 may serve as a potential therapeutic target for HCC in future.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0903-3) contains supplementary material, which is available to authorized users.

Oncogenic Network and Hub Genes for Natural Killer/T-Cell Lymphoma Utilizing WGCNA

“…LMO3 could promote gastric cancer cell invasion and proliferation through Akt-mTOR and Akt-GSK3β signaling pathways (25). In hepatocellular carcinoma, LMO3 directly interacts with LATS1 and suppressing Hippo signaling to promote invasion and metastasis (26). LMO3 interacts with the DNA binding domain of P53 to inhibit its activity (27).…”

Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma

“…The oncogenic role of LMO3 was first described in neuroblastoma, where LMO3 deregulated expression was associated with genesis and progression of neuroblastoma. 81 Since then, increasing evidence suggests that LMO3 could promote cancer cell proliferation, invasion, and metastasis in hepatocellular carcinoma, 82 gastric cancer, 83 clear cell renal cell OR SNP: odds ratio for meta-analysis of SNP main effect; P SNP : P for meta-analysis of SNP main effect. OR GÂS: odds ratio for meta-analysis of 1df.…”

<p>Hypoxia-Induced Placenta-Specific microRNA (miR-512-3p) Promotes Hepatocellular Carcinoma Progression by Targeting Large Tumor Suppressor Kinase 2</p>

“…45,46 The In HCC Hippo signaling acts as a cancer suppression pathway by inhibiting tumor-related processes, including proliferation, 48 migration, 49 and invasion. 50 In the Hippo pathway LATS kinases phosphorylate YAP and cause the cytoplasmic retention and degradation of YAP. In previous studies various microRNAs have been linked to LATS2 regulation in human cancers, including miR-372 in breast cancer, 27 miR-492 in retinoblastoma, 51 miR-135b in cutaneous melanoma, 52 miR-363 in ovarian cancer, 53 and miR-103 in HCC.…”