Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma

Hung Wei Pan, Han Yi E Chou, Shu Hsiang Liu, Shian Yang Peng, Chao Lien Liu, Hey Chi Hsu

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocelllular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization, and RNAi to analyze its role in tumor cell growth. L2DTL protein located to the nucleus in interphase and centered to centrosomes, with colocalization of γ-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with γ-tubulin. L2DTL gene expression increased during G1/S phase, and the DNA sysnthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the APC/C-Cdh1 complex. L2DTL was downregulated in the induced differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth and invasion capability in vitro, in which microarray analysis disclosed dysregulation of genes involved in cell cycle regulation, chromosome segregation, and cell division. L2DTL overexpressed in 59% of 270 resected, unifocal, primary HCCs. L2DTL overexpression correlated with bigger tumor (p=0.000003), high-grade (p=0.00003), and high-stage tumors with portal vein invasion (p=1×10 -8). L2DTL overexpression was associated with a lower 10-year survival, particularly in the p53-mutated HCCs (p=0.00006). In conclusion, L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation, which leads to the loss of p53-governed checkpoints, toward advanced HCC with poor prognosis.

Original languageEnglish
Pages (from-to)2676-2687
Number of pages12
JournalCell Cycle
Volume5
Issue number22
Publication statusPublished - Nov 15 2006
Externally publishedYes

Fingerprint

Centrosome
Nuclear Proteins
Hepatocellular Carcinoma
Cell Cycle
Cells
Tumors
Cell growth
Tubulin
RNA Interference
Carcinoma
Mitosis
Neoplasms
Proteins
Down-Regulation
Chromosome Segregation
Liver Regeneration
Cytokinesis
DNA
Interphase
Hep G2 Cells

Keywords

  • Cell cycle
  • Cell differentiation
  • Centrosome
  • L2DTL
  • Liver regeneration
  • p53 mutation
  • Portal vein invasion

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Pan, H. W., Chou, H. Y. E., Liu, S. H., Peng, S. Y., Liu, C. L., & Hsu, H. C. (2006). Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. Cell Cycle, 5(22), 2676-2687.

Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. / Pan, Hung Wei; Chou, Han Yi E; Liu, Shu Hsiang; Peng, Shian Yang; Liu, Chao Lien; Hsu, Hey Chi.

In: Cell Cycle, Vol. 5, No. 22, 15.11.2006, p. 2676-2687.

Research output: Contribution to journalArticle

Pan, HW, Chou, HYE, Liu, SH, Peng, SY, Liu, CL & Hsu, HC 2006, 'Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma', Cell Cycle, vol. 5, no. 22, pp. 2676-2687.
Pan, Hung Wei ; Chou, Han Yi E ; Liu, Shu Hsiang ; Peng, Shian Yang ; Liu, Chao Lien ; Hsu, Hey Chi. / Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma. In: Cell Cycle. 2006 ; Vol. 5, No. 22. pp. 2676-2687.
@article{59c63b427796441fa0f865bc3d6b6a09,
title = "Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma",
abstract = "L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocelllular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization, and RNAi to analyze its role in tumor cell growth. L2DTL protein located to the nucleus in interphase and centered to centrosomes, with colocalization of γ-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with γ-tubulin. L2DTL gene expression increased during G1/S phase, and the DNA sysnthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the APC/C-Cdh1 complex. L2DTL was downregulated in the induced differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth and invasion capability in vitro, in which microarray analysis disclosed dysregulation of genes involved in cell cycle regulation, chromosome segregation, and cell division. L2DTL overexpressed in 59{\%} of 270 resected, unifocal, primary HCCs. L2DTL overexpression correlated with bigger tumor (p=0.000003), high-grade (p=0.00003), and high-stage tumors with portal vein invasion (p=1×10 -8). L2DTL overexpression was associated with a lower 10-year survival, particularly in the p53-mutated HCCs (p=0.00006). In conclusion, L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation, which leads to the loss of p53-governed checkpoints, toward advanced HCC with poor prognosis.",
keywords = "Cell cycle, Cell differentiation, Centrosome, L2DTL, Liver regeneration, p53 mutation, Portal vein invasion",
author = "Pan, {Hung Wei} and Chou, {Han Yi E} and Liu, {Shu Hsiang} and Peng, {Shian Yang} and Liu, {Chao Lien} and Hsu, {Hey Chi}",
year = "2006",
month = "11",
day = "15",
language = "English",
volume = "5",
pages = "2676--2687",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "22",

}

TY - JOUR

T1 - Role of L2DTL, cell cycle-regulated nuclear and centrosome protein, in aggressive hepatocellular carcinoma

AU - Pan, Hung Wei

AU - Chou, Han Yi E

AU - Liu, Shu Hsiang

AU - Peng, Shian Yang

AU - Liu, Chao Lien

AU - Hsu, Hey Chi

PY - 2006/11/15

Y1 - 2006/11/15

N2 - L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocelllular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization, and RNAi to analyze its role in tumor cell growth. L2DTL protein located to the nucleus in interphase and centered to centrosomes, with colocalization of γ-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with γ-tubulin. L2DTL gene expression increased during G1/S phase, and the DNA sysnthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the APC/C-Cdh1 complex. L2DTL was downregulated in the induced differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth and invasion capability in vitro, in which microarray analysis disclosed dysregulation of genes involved in cell cycle regulation, chromosome segregation, and cell division. L2DTL overexpressed in 59% of 270 resected, unifocal, primary HCCs. L2DTL overexpression correlated with bigger tumor (p=0.000003), high-grade (p=0.00003), and high-stage tumors with portal vein invasion (p=1×10 -8). L2DTL overexpression was associated with a lower 10-year survival, particularly in the p53-mutated HCCs (p=0.00006). In conclusion, L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation, which leads to the loss of p53-governed checkpoints, toward advanced HCC with poor prognosis.

AB - L2DTL is a human ortholog of Drosophila lethal (2) denticleless, l(2)dtl. This study is to elucidate its function and clinicopathological significance in hepatocelllular carcinoma (HCC) progression. We used RT-PCR, immunostaining, Western blotting, and centrosome isolation to determine the L2DTL expression and protein localization, and RNAi to analyze its role in tumor cell growth. L2DTL protein located to the nucleus in interphase and centered to centrosomes, with colocalization of γ-tubulin and Aurora-A, throughout the cell cycle, and cofractionated with γ-tubulin. L2DTL gene expression increased during G1/S phase, and the DNA sysnthesis in liver regeneration. L2DTL protein decreased in mitosis via degradation by the APC/C-Cdh1 complex. L2DTL was downregulated in the induced differentiation of HepG2 and NT2 cells. L2DTL downregulation by RNAi oligos led to reduced cancer cell growth and invasion capability in vitro, in which microarray analysis disclosed dysregulation of genes involved in cell cycle regulation, chromosome segregation, and cell division. L2DTL overexpressed in 59% of 270 resected, unifocal, primary HCCs. L2DTL overexpression correlated with bigger tumor (p=0.000003), high-grade (p=0.00003), and high-stage tumors with portal vein invasion (p=1×10 -8). L2DTL overexpression was associated with a lower 10-year survival, particularly in the p53-mutated HCCs (p=0.00006). In conclusion, L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. L2DTL overexpression is associated with enhanced metastatic potential of HCC, and contributes synergistically with p53 mutation, which leads to the loss of p53-governed checkpoints, toward advanced HCC with poor prognosis.

KW - Cell cycle

KW - Cell differentiation

KW - Centrosome

KW - L2DTL

KW - Liver regeneration

KW - p53 mutation

KW - Portal vein invasion

UR - http://www.scopus.com/inward/record.url?scp=33751232623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33751232623&partnerID=8YFLogxK

M3 - Article

C2 - 17106265

AN - SCOPUS:33751232623

VL - 5

SP - 2676

EP - 2687

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 22

ER -