RUNX3 gene methylaton detection: A novel target for the diagnosis and treatment of ovarian cancer

Introduction

The human runt-related transcription factor 3 gene (RUNX3), a novel tumor suppressor, was originally cloned as AML2 in human leukocythemia by Levanon in 1994 and is located on human chromosome 1p36.1^[1]. RUNX3 contains two promoters, p1 and p2, one at the beginning of exon 1 and the other in front of exon 2. The mRNA expression of RUNX3 comes from transcription by p2, which has a high GC content due to a large conserved CpG island around it and contains Sp1 sites and a CCAAT box without a TATA box. It is an important target of transforming growth factor TGF-ß superfamily signaling.  山东大学齐鲁医院妇科张师前

Recently, RUNX3 has been considered to be a vital gene in the occurrence and development of many carcinoma^[2].Present study indicated Runx3 geng expression silenced is associated with promoter hypermethylation.furthermore,Runx3 promoter hypermethylation has been demonstrated in 73% hepatic cellular cancer；64% gastric cancer；62% laryngeal carcinoma；25% breast cancer；23% prostatic carcinoma；24% lung cancer et al^[3,4].5-aza-2-deoxycytidine is a DNA methylation transferring enzyme suppressive agent,can reversal promoter hypermethylation of gene in vitro.Extraorgan investigation indicate that the tumor cells without RUNX3 gene expression were co-cultivation with 5-aza-2-deoxycytidine will re- expression. such as gastric cancer cells^[5]；lung cancer cells^[4]； cholangiocarinoma cancer cells^[6]； pancreatic cancer cells^[6]； HCC cells^[7] and breast cancer cells^[8]. The results confirm that the RUNX3 gene expression down regulation was associated with  its promoter hypermethylation. however, It has been reported that RUNX3 gene promoter hypermeyhylation was not to be present in nasopharyngeal carcinoma^[9]. Although these findings are inconsistent, they suggest that RUNX3 promoter hypermethylation has an important function in tumor development and progression.

The tumor are common characterized by a large anount of hyperproliferation and poorly differentiated or undifferentiated cells in it.Now that RUNX3 plays an important role in many tumor development and progression,did it play an important role in the ovarian canaers?

It is well known that ovarian cancer is characterized by high diseaseincidence and high case fatality. So，to look for the new target for early diagnosis and effective therapeutic tool is the key point to improve ovarian cancer status quo.

Multiple genes and multiple  procedures participate in the occurrence and development of ovarian carcinoma，which is at the top list of malignant tumors？ Deactivation of anti-oncogenes is more frequent than activation of proto-oncogenes in the ovarian carcinogenesis process. Anti-oncogenes are devitalized by chromosomal absence, gene mutation, and aberrant CpG island hypermethylation of gene promoters^[10,11]. Recentely study showed that CpG island hypermethylation is the most mechanisms in tumor development,morever some scholars presume that is only one mechanism in tumor development.Therefore ,Identification the genes promoter hypermethylation may shed light on the prevention and cure of  ovarian cancer.

Several genes have been demonstrated that promoter hypermethylation was associated with the occurrence and development of ovarian carcinoma

Choi^[12] et al confirm that RASSFIA gene promoter region methylation will be a target of molecular biology by MSP(methylation spectial PCR), Can detection the  occurrence and development of ovarian cancer. Wang bo et al confirm that FHIT gene promoter methylation was associated with ovarian cancers occurrence and development, as well a early occurrence in ovarian cancer.  Katsaron^[13] et al study indicated that p16 gene promoter methylation was associated with ovarian cancers occurrence and prognostic.

The results above demonstrated that the promoter methylation is the most mechanism of ovarian cancer, and a early occurrence in ovarian canaer. and the phenomenon of methylation will be reversed by DNA methylation transferring enzyme suppressive agent. But the ovarian carcinoma occurrence is a process with multiple genes participate. So，The key point of ovarian canaer early diagnosis is combination detection polygene.

Hypotheses

As the most tumor that ovaria cancer was characterized by a large anount of hyperproliferation and poorly differentiated or undifferentiated cells. As a anti-oncogene RUNX3 can carry out cytostasis and proceeding apoptosis effect by transforming growth factor beta1(TGF-ß1)-dependent.In many malignant tumors of mankind RUNX3 proteinum expression down regulation even absence because of promorter hypermethylation，Induce TGF-ß1 signal transduction system deactivation. and induce the tumors occurrence. As a new anti-oncogene RUNX3 express generally in many tissues and cells and ovary. so RUNX3 may be plays an important role in ovarian cancer,therefor detection RUNX3 promorter methylation may be a novel target for the diagnosis and treatment of ovarian cancer.