Abstract
Chemoresistance often occurs during 5-fluorouracil (5-Fu) treatment of colorectal cancer (CRC). It is significant to explore the potential strategies to sensitize colorectal cancer cells to 5-Fu treatment. We studied the sensitization of Nephroblastoma overexpressed protein (NOV) on 5-Fu treatment. NOV was overexpressed and knocked down in HT115 and RKO cells respectively. Cell proliferation experiments and related mechanism studies by RT-qPCR and Western blot were performed Subsequently. Nude mouse xenograft model was established to test the inhibitory effect of 5-FU on CRC cells in vivo. In this study, we found that NOV mRNA expression was significantly lower in tumor tissues than that in the normal tissues (P < 0.05). The cell proliferation was reduced in the HT115-NOVexp groups (P < 0.05) and increased in the RKO-NOVkd groups (P < 0.05) than that in the control groups and NC groups. The RT-PCR and Western Blot results showed that NOV inhibited the expression of activator protein (AP)-1 (P < 0.05) and promoted the expression of Caspase-8/3 (P < 0.05) in CRC cells in vitro. NOV also improved the inhibitory effect of 5-Fu on inhibiting colorectal cancer proliferation in a tumor cell xenotransplantation nude mouse model. NOV inhibited the expression of AP-1 and JUK and promoted the expression of Caspase-8/3 in cancer tissues in a tumor cell xenotransplantation nude mouse model. In summary, NOV can sensitize CRC cells towards 5-Fu-mediated inhibitory effect on cell proliferation and its sensitization may be achieved by the JNK/AP-1/Caspase-8/Caspase-3 pathway.
Highlights
The incidence and mortality of colorectal cancer (CRC) are increasing every year, greatly threatening the health of humans [1]
We examined the Nephroblastoma overexpressed protein (NOV) mRNA expression in CRC and adjacent normal tissues and found that NOV mRNA expression was significantly lower in tumor tissues than that in the normal tissues (P < 0.05) (Fig. 1a)
3.2 NOV inhibited the expression of activator protein (AP)‐1 and promoted the expression of Caspase‐8/3 in CRC cells in vitro
Summary
The incidence and mortality of colorectal cancer (CRC) are increasing every year, greatly threatening the health of humans [1]. CRC ranked third in men and second in women of the new cases of malignant tumors worldwide [2, 3]. More than half of the patients with CRC cannot benefit from the current first-line treatment program. 5-FU exerts anticancer effects by inhibiting tumor cell proliferation and promoting apoptosis [8]. Some studies have shown that NOV exerts an inhibitory function in some malignant solid tumors [13,14,15,16]. Fukunaga-Kalabis et al found that NOV inhibited the invasion of melanoma cells by inhibiting matrix metalloproteinase-2/-9 ( MMP-2/-9), which suggested that low expression of NOV might be a possible mechanism for melanoma progression [13]. We focused on the sensitization of NOV on 5-Fu treatment of CRC by in vitro and in vivo experiments
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