Cervical cancer
Life span
2007/7-11/24
Int J Oncol. 2007
Aug;31(2):361-8. Zhao
P, Wang
C, Fu
Z, You
Y, Cheng
Y, Lu
X, Lu
A, Liu
N, Pu P, Kang
C, Salford LG, Fan
X. Department of Neurosurgery,
The First Affiliated Glioma
cells are characterized by their invasiveness and resistance against
conventional therapeutics. Telomerase activity has been suggested to be an
important target for glioma treatment. Here we
assessed the anticancer effects and its potential mechanisms of lentiviral vector mediated siRNA
knock-down of the human telomerase reverse transcriptase (hTERT) in U87MG human glioblastoma
cells. Stable expression of anti-hTERT siRNA reduced the hTERT
expression and TRAP assay telomerase activity to barely detectable levels.
Injection of lentiviral vectors encoding anti-hTERT siRNA significantly
inhibited the growth of pre-established macroscopic xenograft
tumors, which was in contrast to the finding that no obvious effects on
cell growth, cell cycle progression and telomere length were observed in
anti-hTERT siRNA
expressing U87MG cells during short-term in vitro cultures. The in vivo glioma growth inhibition effect was already evident in
the period coincided with no detectable telomere length changes, suggesting
that hTERT inhibition may hinder glioma cell growth in a telomere length-independent
manner. Importantly, transwell migration assay
showed profound inhibitory effect on the invasive capacity of U87MG cells
following short-term anti-hTERT siRNA expression. Thus, efficient knock-down of hTERT can inhibit glioma cell
proliferation and migration prior to its effect on telomere length. PMID: 17611693 [PubMed
- in process] Mol Biol Cell. 2005 Mar;16(3):1491-9.
Epub 2005 Jan 12. Terai M, Uyama T, Sugiki T, Li
XK, Umezawa A, Kiyono T. Department
of Reproductive Biology and Pathology, National Research Institute for
Child Health and Development, Human umbilical cord
blood-derived mesenchymal stem cells (UCBMSCs) are expected to serve as an excellent
alternative to bone marrow-derived human mesenchymal
stem cells. However, it is difficult to study them because of their limited
life span. To overcome this problem, we attempted to produce a strain of UCBMSCs with a long life span and to investigate
whether the strain could maintain phenotypes in vitro. UCBMSCs
were infected with retrovirus carrying the human telomerase reverse
transcriptase (hTERT) to prolong their life span.
The UCBMSCs underwent 30 population doublings (PDs) and stopped dividing at PD 37. The UCBMSCs newly established with hTERT
(UCBTERTs) proliferated for >120 PDs. The p16INK4a/RB braking pathway leading to
senescence can be inhibited by introduction of Bmi-1, a polycomb-group
gene, and human papillomavirus type 16 E7, but
the extension of the life span of the UCBMSCs
with hTERT did not require inhibition of the
p16INK4a/RB pathway. The characteristics of the UCBTERTs
remained unchanged during the prolongation of life span. UCBTERTs provide a powerful model for further study of
cellular senescence and for future application to cell-based therapy by
using umbilical cord blood cells. PMID: 15647378 [PubMed
- indexed for MEDLINE] Mol Cell
Biol. 2002 Jul;22(14):5157-72. Rheinwald JG, Hahn
WC, Ramsey
MR, Wu
JY, Guo Z, Tsao H, De
Luca M, Catricalà C, O'Toole
KM. Department
of Dermatology, Brigham and Women's Hospital, With increasing frequency during
serial passage in culture, primary human keratinocytes
express p16(INK4A) (p16) and undergo senescence
arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not
immortalized unless, by mutation or other heritable event, they avoid or
greatly reduce p16 expression. We have confirmed that keratinocytes
undergo p16-related senescence during growth in culture, whether in the
fibroblast feeder cell system or in the specialized K-sfm
medium formulation, and that this mechanism can
act as a barrier to immortalization following hTERT
expression. We have characterized the p16-related arrest mechanism more
precisely by interfering specifically with several regulators of cell cycle
control. Epidermal, oral mucosal, corneal limbal,
and conjunctival keratinocytes
were transduced to express a p16-insensitive
mutant cdk4 (cdk4(R24C)), to abolish p16 control,
and/or a dominant negative mutant p53 (p53DD), to abolish p53 function.
Expression of either cdk4(R24C) or p53DD alone had little effect on life
span, but expression of both permitted cells to divide 25 to 43 population
doublings (PD) beyond their normal limit. Keratinocytes
from a p16(+/-) individual transduced
to express p53DD alone displayed a 31-PD life span extension associated
with selective growth of variants that had lost the wild-type p16 allele.
Cells in which both p53 and p16 were nonfunctional divided rapidly during
their extended life span but experienced telomere erosion and ultimately
ceased growth with very short telomeres. Expression of hTERT
in these cells immortalized them. Keratinocytes
engineered to express cdk4(R24C) and hTERT but not p53DD did not exhibit an extended life
span. Rare immortal variants exhibiting p53 pathway defects arose from
them, however, indicating that the p53-dependent component of keratinocyte senescence is telomere independent.
Mutational loss of p16 and p53 has been found to be a frequent early event
in the development of squamous cell carcinoma.
Our results suggest that such mutations endow keratinocytes
with extended replicative potential which may
serve to increase the probability of neoplastic
progression. PMID: 12077343 [PubMed
- indexed for MEDLINE Xi Bao Yu Fen Zi
Mian Yi Xue Za Zhi.
2007 Jul;23(7):638-40. [Article in Chinese] Zhang
M, Xin XY, Li
HM, Song
H. Department
of Obstetrics and Gynecology, AIM: To investigate the effect
of hTERT promoter which regulated tumor targeting
TRALL on the cervical cancer cell line HeLa.
METHODS: The mRNA expression of TRAIL on HeLa was
examined by RT-PCR. The proliferation, apoptosis, motion
of the transfected cervical cancer cell were
detected by MTT, flow cytometry, and cell
invasion assay respectively. The ultrastructure
was observed by electron microscope. RESULTS: Compared with the control
group, the expression of TRAILmRNA was
significantly upregulated in hTERT-TRAIL
(P<0.05). The apotosis rate and the inhibitory
rate of cell growth of hTERT-TRAIL was
significantly high (P<0.05). Electron microscope results indicated that hTERT promoter regulated tumor targeting TRALL
facilitated the apoptosis of HeLa. CONCLUSION:
The hTERT-TRAIL significantly inhibits the
malignant proliferation and invasion ability of the cervical cancer cell
line, and facilitates the apoptosisof HeLa, which lays a foundation for the treatment of
patients with cervical cancer. PMID: 17618588 [PubMed
- in process]
Lentiviral vector
mediated siRNA knock-down of hTERT
results in diminished capacity in invasiveness and in vivo growth of human glioma cells in a telomere length-independent manner.
Immortalization of human fetal cells: the life
span of umbilical cord blood-derived cells can be prolonged without
manipulating p16INK4a/RB braking pathway.
A two-stage, p16(INK4A)-
and p53-dependent keratinocyte senescence
mechanism that limits replicative potential
independent of telomere status.
[hTERT
promoter regulated tumor targeting TRALL in cervical cancer cell.]