Somatic LMCD1 mutations promoted cell migration and tumor metastasis in hepatocellular carcinoma

Abstract

Common genetic alteration in cancer genomes is implicated for embracing an aberrant cancer gene participated in tumor progression. In this study, we identified a somatic mutated LIM and cysteine-rich domains-1 (LMCD1) as a putative metastatic oncogene in human hepatocellular carcinoma (HCC) using integrated genomic approaches. In addition to revealing genomic amplification and gene upregulation, we identified recurrent E135K (3/48 cases) mutations in HCC tissues and K237R mutation in the PLC/PRF/5 HCC cell line. Expression of mutant LMCD1 E135K or K237R reduced the stress fiber assembly, increased cortical actin accumulation and induced lamellipodial extension. Consistently, these mutations enhanced cell migration and showed activation of the Rac1-signaling pathway. Inhibition of the LMCD1/Rac1 pathway by an LMCD1 short-hairpin RNA (shLMCD1) or the Rac1 inhibitor NSC23766 suppressed the mutationmediated lamellipodial protrusion and cell migration. In PLC/PRF/5 cells with endogenous K237R mutation, cell migration was enhanced by estrogen-induced LMCD1 expression but reversed by shLMCD1 treatment. Moreover, overexpression of LMCD1 E135K mutation significantly promoted systemic lung metastasis in a murine tail vein injection model. Together, our results suggest that LMCD1 mutations are potential oncogenic events in HCC metastasis to promote cell migration through the Rac1-signaling pathway.

Transcriptome profiling reveals novel gene expression signatures and regulating transcription factors of TGFβ‐induced epithelial‐to‐mesenchymal transition

“…LMCD1 was previously described as a transcriptional co‐repressor of GATA6, whereas its role in cytoskeletal compartments remains to be elucidated 32. LMCD1 E135K somatic mutation was associated with cell migration and tumor metastasis in hepatocellular carcinoma (HCC); its up‐regulation was also positively correlated with infiltrative tumor growth patterns in HCC patients, implying its possible involvement in tumor cell invasiveness 33. Our data directly reveal for the first time to our knowledge that upregulated LMCD1 may intermediate EMT progression and contribute to tumor cell invasiveness and metastasis.…”

RAC1: An Emerging Therapeutic Option for Targeting Cancer Angiogenesis and Metastasis

“…D4-GDI associates with RAC1 and RAC3 in these cell lines, but not with other RHO GTPases. The exact mechanism that mediates this phenomenon has not been elucidated, but the loss of D4-GDI inhibition appears to block anchorage-independent growth, restore anoikis, and induce apoptosis[31]. …”

“…Hepatocellular carcinomas often harbor activating mutations in LMCD1, a downstream target of RAC, that increase lamellipodial protrusion and augment the metastatic virulence of the tumor cells carrying the mutation(31). In other HCC patient samples and cell lines, microRNA-142-3p (miR-142-3p) targets RAC1 expression by binding to the 3′UTR of RAC1(32).…”

TRAIL-coated leukocytes that kill cancer cells in the circulation

“…5A). Tail-vein injection was used to model leukocyte/CTC interactions in mouse circulation, as this technique has been an accepted and widely used model of lung metastasis (28)(29)(30)(31) since the pioneering work of Fidler et al (32)(33)(34). For these studies, the use of recombinant human E-selectin was continued because of its ability to bind both human COLO 205 cancer cells and mouse neutrophils, which were previously shown to have cross-reactivity and roll on E-selectin (35).…”