Major Project
Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer
Wang et al. (2014)
conducted a study to investigate roles of ribonucleotide reductase M2 (RRM2) as
a novel potential target activated by human papillomavirus (HPV) E7 oncoprotein
on cervical cancer progression. In previous studies (Rosty et al., 2005; Kuner
et al., 2007) found many novel potential downstream genes for HPVE7 oncoprotein
by microarray technique, RRM2 is the one of novel potential downstream genes
for HPVE7 oncoprotein. In addition, overexpression RRM2 is also associated with
tumor angiogenesis and tumor metastasis (Zhang et al., 2009; Zhou et al.,
1998.) The study was divided into three parts; cell culture, animal, and human
specimen experiments. In cell culture, HeLa cell line, a positive HPV type 18
cervical cell line which has HPVE7 oncoprotein, and C33A cell line, a negative
HPV which has no HPV oncoprotein, were used in the study. C33A cell line was
transfected with plasmid for HPVE7 for biochemical characterization as HeLa
cell line to confirm results of roles of RRM2 on cervical cancer progression.
In animal experiment, BALB/c nude mice were inoculated subcutaneously with 5x106
C33A-transfected RRM2 (C33A-RRM2) and C33A-transfected empty vector (C33A-V).
In human specimen experiment, human cervical cancer samples were collected from
cervical cancer patients to stain immunohistochemistry for RRM2 and CD31, an angiogenesis
biomarker, expressions. The results showed RRM2 as a novel target for HPVE7 to
mediated cervical cancer progression in all parts of experiment. Therefore, RRM2 may be a therapeutic target
for cervical cancer treatment or a biomarker for predicting the prognosis of
cervical cancer in the future.
This provides a novel target downstream activated of
HPVE7 to mediate cervical cancer progression. However, there are some
limitations.
1. This
study chose only positive HPV type 18 cancer cell line (HeLa cells). The
research may choose other positive HPV type 16 cancer cell lines such as CaSki
cells to confirm their results.
2. For
animal experiment, the study used nude mice-transplanted C33A-RRM2 only to determine
the roles of RRM2 in cervical cancer progression. The study may use the posivtive
HPVE7 cell line together to confirm the in vivo results.
3. For
human specimen, the study should determine correlation between RRM2 expression
and cervical cancer stage for more information for predicting the prognosis of
cervical cancer in the future.
The strength of the study is that the confirmation of
supporting roles of RRM2 in cervical cancer progression in positive HPVE7 HeLa
cell line by comparing to negative HPVE7 C33A cell line which were transfected with
RRM2.
References:
1. Wang, N., Zhan, T., Ke, T., Huang, X., Ke, D.,
Wang, Q., & H, Li. (2014). Increased expression of RRM2 by human
papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer. Br J
Cancer. 18; 110(4):1034-44.
2. Rosty, C., Sheffer, M., Tsafrir, D., Stransky, N.,
Tsafrir, I., Peter, M., & et al. (2005). Identification of a proliferation
gene cluster associated with HPV E6/E7 expression level and viral DNA load in
invasive cervical carcinoma. Oncogene. 27; 24(47):7094-104.
3. Kuner, R., Vogt, M., Sultmann, H., Buness, A.,
Dymalla, S., Bulkescher, J., & et al. (2007). Identification of cellular
targets for the human papillomavirus E6 and E7 oncogenes by RNA interference
and transcriptome analyses. J Mol Med (Berl). 85(11):1253-62. Epub 2007
Jun 23.
4. Zhang,
K., Hu, S., Wu, J., Chen, L., Lu, J., Wang, X., et al. (2009). Overexpression
of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer
cells in vitro and in vivo: implication of RRM2 in angiogenesis. Mol Cancer.
28;8:11.
5. Zhou, B.,S., Tsai, P., Ker, R., Tsai, .J, Ho, R’,
Yu, J., et al. (1998). Overexpression of transfected human ribonucleotide
reductase M2 subunit in human cancer cells enhances their invasive potential. Clin
Exp Metastasis. 16(1):43-9.
