Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma

PLoS One. 2013 Nov 14;8(11):e80053. doi: 10.1371/journal.pone.0080053. eCollection 2013.

Abstract

By using an expressed sequence tag bioinformatic algorithm, we identified that Lin28 homolog B (Lin28B) may have an oncofetal expression pattern which may facilitate detecting cancer cells in adults. It is also reported to be a potential marker for cancer stem cells. Therefore, we sought to verify oncofetal-stemness characters of Lin28B and test its potential as a circulating cancer stem cell-like marker in adult HCC patients. Lin28B mRNA was examined in a panel of fetal tissue, adult tissue and tumors. Lin28B was over-expressed or knocked down in HepG2 cells to evaluate its potential as a stem cell-like marker. RT-qPCR for Lin28B was performed in the peripheral blood mononuclear cells from patients with HCC receiving surgery (n=96) and non-HCC controls (n=60) and analyzed its clinical significance. Lin28B showed an oncofetal expression pattern. Its overexpression could upregulate stemness markers (OCT4, Nanog and SOX2) and enhance tumorsphere formation in vitro. Lin28B knockdown had opposite effects. Circulating Lin28B was detected in peripheral blood mononuclear cells in 3 cases (5%) of non-HCC controls and 32 cases (33.3%) of HCC patients. In HCC patients, circulating Lin28B was associated with high tumor grade (P=0.046), large size (P=0.005), high AJCC stage (P=0.044) and BCLC stage (P=0.017). Circulating Lin28B was significantly associated with decreased recurrence-free survival (P<0.001). Circulating Lin28B separated early stage HCC into 2 recurrence-free survival curves (P=0.003). In multivariate analysis, circulating Lin28B was an independent variable associated with early recurrence (P=0.045) and recurrence in early stage HCC (P=0.006). In conclusion, the oncofetal gene Lin28B is a potential oncofetal cancer-stem-cell-like circulating tumor cell marker that correlates with HCC recurrence after hepatectomy. Circulating Lin28B could refine early AJCC stages. Our finding supports the possible use of a TNMC (C for circulating tumor cells) staging system in HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / surgery
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Hep G2 Cells
  • Hepatectomy
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Liver Neoplasms / surgery
  • Male
  • Middle Aged
  • Nanog Homeobox Protein
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / mortality
  • Neoplasm Recurrence, Local / pathology
  • Neoplasm Recurrence, Local / surgery
  • Neoplasm Staging
  • Neoplastic Cells, Circulating / metabolism
  • Neoplastic Cells, Circulating / pathology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Survival Analysis

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • LIN28B protein, human
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3
  • POU5F1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • SOX2 protein, human
  • SOXB1 Transcription Factors

Grants and funding

This was supported by grant DOH101-TD-C-111-003 from the Department of Health, Taiwan, grant NSC 97-2320-B-006 -027 -MY3 and grant NSC-99-2628-B-006-034-MY2 from the National Science Council, Taiwan, and NCKUH Research Grant (95) No. 67 from National Cheng Kung University Hospital, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.