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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 mutation-mediated 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.

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Acknowledgements

We thank Dr Pei-Jer Chen and Dr Ding-Shinn Chen at School of Medicine, National Taiwan University, for helpful discussions and advice on the work. We also thank the core facilities from National Research Program for Genomic Medicine, National Science Council, Taiwan, including the National Genotyping Center, for their service in SNP genotyping and the National RNAi Core facility for providing shRNAs. Financial Support: This work was funded by the National Research Program for Genomic Medicine of the National Science Council, Taiwan, through grant numbers NSC98-3112-B-001-004, NSC98-3112-B-001-031 and NSC99-3112-B-001-019.

Author contributions: C-YC, S-CL and C-MH performed the experiments; C-YC, W-HS, C-MH and Y-SJ performed data analysis and interpretation; and C-YC and Y-SJ drafted the manuscript and supervised the study.

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Correspondence to Y-S Jou.

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Chang, CY., Lin, SC., Su, WH. et al. Somatic LMCD1 mutations promoted cell migration and tumor metastasis in hepatocellular carcinoma. Oncogene 31, 2640–2652 (2012). https://doi.org/10.1038/onc.2011.440

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  • DOI: https://doi.org/10.1038/onc.2011.440

Keywords

  • somatic mutations
  • LMCD1
  • LIM domain
  • metastasis
  • hepatocellular carcinoma

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