Abstract
The double stranded small active RNA (saRNA)- p21-saRNA-322 inhibits tumor growth by stimulating the p21 gene expression. We focused our research of p21-saRNA-322 on colorectal cancer because 1) p21 down-regulation is a signature abnormality of the cancer, and 2) colorectal cancer might be a suitable target for in situ p21-saRNA-322 delivery. The goal of the present study is to learn the activity of p21-saRNA-322 in colorectal cancer. Three human colorectal cancer cell lines, HCT-116, HCT-116 (p53–/−) and HT-29 were transfected with the p21-saRNA-322. The expression of P21 protein and p21 mRNA were measured using the Western blot and reverse transcriptase polymerase chain reaction (RT-PCR). The effect of p21-saRNA-322 on cancer cells was evaluated in vitro; and furthermore, a xenograft colorectal tumor mode in mice was established to estimate the tumor suppressing ability of p21-saRNA-322 in vivo. The results showed that in all three colorectal cancer cell lines, the expression of p21 mRNA and P21 protein were dramatically elevated after p21-saRNA-322 transfection. Transfection of p21-saRNA-322 caused apoptosis and cell cycle arrest at the G0/G1. Furthermore, anti-proliferation effect, reduction of colonies formation and cell senescence were observed in p21-saRNA-322 treated cells. Animal studies showed that p21-saRNA-322 treatment significantly inhibited the HT-29 tumor growth and facilitated p21 activation in vivo. These results indicated that, p21-saRNA-322-induceded up-regulation of p21 might be a promising therapeutic option for the treatment of colorectal cancer.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death worldwide [1]
The p21-small active RNA (saRNA)-322 was used to activate p21 expression, in which HCT-116, HCT-116 (p53–/–) and HT-29 cells were transfected with 25 nM of p21saRNA-322 using scramble RNA as well as the untreated as references. 24, 48 and 72 hrs later, the expression of p21 mRNA was tested by reverse-transcriptase polymerase chain reaction (RT-PCR) and P21 protein level was analyzed with Western blot
We investigated whether the introduction of p21-saRNA-322 could activate p21 gene expression in the colorectal cancer cells, and whether the activity of p21saRNA-322 was influenced by intrinsic p21 expression and p53 integrity
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death worldwide [1]. In addition to inhibiting CDK activity, P21 binds to proliferating cell nuclear antigen (PCNA) and prevents it from activation of DNA polymerase, an activity required for DNA replication and repair. It plays an important role in regulating the proliferation, apoptosis, differentiation [5,6,7], metastasis [8] and stemness of cancer cells [9]. The losses of both expression and topological regulation of p21 is commonly detected in colorectal cancer [10]
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