Downregulation of Mus81 as a novel prognostic biomarker for patients with colorectal carcinoma

Abstract

The Mus81 gene encodes a critical endonuclease involved in DNA repair and tumor suppression. Our previous study has shown reduced expression of Mus81 in hepatocellular carcinoma and its association with the metastastic potential and prognosis of hepatocellular carcinoma. However, the role of Mus81 in colorectal carcinoma is currently unknown. We therefore carried out the present study to explore the correlation between Mus81 expression and the progression of colorectal carcinoma. Mus81 expression in 92 cases of colorectal carcinoma and matched normal tissues was determined by quantitative real-time polymerase chain reaction. Our results showed that Mus81 expression in colorectal carcinoma tissues was significantly reduced compared with the corresponding normal tissues (P < 0.001) and the downregulation of Mus81 (decreased by more than 50%) was found in 60.9% (56/92) of colorectal carcinoma. Moreover, Mus81 downregulation correlated significantly to hepatic metastasis (P = 0.019) and a high TNM stage (P = 0.025) of colorectal carcinoma. In addition, the decrease of Mus81 was also detected in 10 cases of hepatic metastasis tissues compared with the corresponding primary colorectal carcinoma tissues (P = 0.016). More importantly, colorectal carcinoma patients with apparent Mus81 downregulation have shown significantly poorer overall survival than those with little Mus81 downregulation (P = 0.0374). Also, multivariable Cox regression analysis identified Mus81 downregulation as an independent prognostic factor for colorectal carcinoma (hazard ratio, 1.678; P = 0.040). In conclusion, the reduced expression of Mus81 is closely related to hepatic metastasis and poor prognosis of colorectal carcinoma, indicating Mus81 as a novel prognostic marker for colorectal carcinoma. (Cancer Sci 2011; 102: 472-477) C olorectal carcinoma (CRC) ranks as the third most common cancer in the world and the incidence of CRC is increasing rather rapidly in the Asia-Pacific region, especially in Japan.(1,2)Up until now, abundant evidence has shown that a variety of genetic and epigenetic alterations in both oncogenes and tumor suppressors are involved in the pathogenesis of CRC. Activation of oncogenes such as the ras gene and the inactivation of tumor suppressors such as APC and p53 genes have been documented in CRC. (3)(4)(5) In addition, we have identified some genetic as well as epigenetic changes related to this disease.(6-11) However, further investigations are still necessary to clarify the tumorigenic pathway of CRC.The Mus81 gene encodes a structure-specific DNA endonuclease, which resolves holliday junctions through constituting a heterodimer with Eme1 ⁄ Mms4 and plays a critical role in the repair of double-strand breaks of DNA and maintenance of chromosomal integrity.(12-15) McPherson et al. (16) have shown that 73% Mus81 ) ⁄ ) mice and 50% Mus81 + ⁄ ) mice died of various spontaneous tumors such as lymphoma, breast cancer and prostate cancer, implicating Mus81 as a potent tumor suppressor in mice. Moreover, Mus81 was found ...

Holliday Junction Resolvases

“…Nonetheless, these mutants exhibit mitotic defects and are hypersensitive to specific DNA-damaging agents, including CPT, cisplatin, and MMC. The observation that MUS81 is down-regulated in hepatocellular and colon carcinoma provides circumstantial evidence that MUS81-EME1 is also required for chromosomal stability in humans (Wu et al 2008(Wu et al , 2011.…”

Molecular characterization and expression analysis of mouse epidermal growth factor-like domain 8

“…EGFL6 is overexpressed in benign meningioma tissues and serum (16). Downregulation of EGFL8 expression has been observed in gastric cancer, and is significantly correlated with high tumor-node-metastasis stage and poor prognosis in gastric and colorectal cancer (17,18). Recent studies by our group have demonstrated that EGFL8 has inhibitory effects on mouse thymic epithelial cells and thymocytes, indicating that it is a negative regulatory molecule in T-cell development in the mouse thymus (19,20).…”

“…First-strand cDNA was obtained via reverse transcription using 2 µg total RNA. The reaction was performed in 20 µl buffer containing 0.5 µg oligo(dT) [12][13][14][15][16][17][18] primer, 50 mM Tris-HCl (pH 8.3), 75 mM KCl, 3 mM MgCl 2 , 40 mM dithiothreitol, 0.5 mM deoxynucleotide triphosphate mixture, 10 units RNase inhibitor and 200 units Moloney murine leukemia virus reverse transcriptase (all from Invitrogen Life Technologies). After incubation at 37˚C for 60 min, the reaction was stopped via heating at 70˚C for 15 min.…”

Upregulation of WEE1 is a potential prognostic biomarker for patients with colorectal cancer

“…The activation of oncogenes such as the ras gene and the inactivation of tumor suppressors such as adenomatous polyposis coli and p53 genes have been well documented in CRC (4)(5)(6). In addition, we previously identified certain genetic changes, including the downregulation of MUS81 structure-specific endonuclease subunit and epidermal growth factor-like protein 8 precursor, to be associated with this malignancy (7,8). However, further investigations are still necessary to clarify the tumorigenic pathway of CRC (9).…”