Knockdown of ovarian cancer amplification target ADRM1 leads to downregulation of GIPC1 and upregulation of RECK

Abstract

Approximately 25,000 ovarian cancers are diagnosed in the United States annually, and 75% of cases are in the advanced stage when they are largely incurable. There is a critical need for improved early detection tools and development of novel treatments. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knockdown of ADRM1 in amplified ovarian cell-line OAW42 results in downregulation of growth factor GIPC1 and upregulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knockdown of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK.

Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer

“…It was amplified and overexpressed in 23% of tumors, was significantly upregulated with respect to stage, recurrence and metastasis, and its overexpression correlates significantly with shorter time to recurrence and overall survival [1]. Consistent with these findings, using array-CGH and RNA expression analysis of ovarian cancer cell lines, we showed the amplification and overexpression of ADRM1 in 18% (7/39) of ovarian cancer cell lines [12]. Herein, CGH analysis of ADRM1 in a separate cohort of 68 primary ovarian carcinomas, including one with high level amplification of a 262 kilobase region containing ADRM1 , provide additional evidence that ADRM1 is the driver of a 20q13 amplicon in ovarian cancer.…”

“…Consistent with these findings, using array-CGH and RNA expression analysis of ovarian cancer cell lines, we showed the amplification and overexpression of ADRM1 in 18% (7/39) of ovarian cancer cell lines [12]. Among these, ovarian cancer cell line OAW42 was found to be amplified and had the highest level of overexpression and was used as a model for knock-down of expression of ADRM1 in ADRM1 -amplified ovarian cancer.…”

Functional proteomics, human genetics and cancer biology of GIPC family members

“…GIPC1 is upregulated in human cancers, such as breast cancer, 25, 28, 29, 32 ovarian cancer 26, 28, 34 and pancreatic cancer. 25, 27, 31 GIPC1 is a cancer-associated auto-antigen, as anti-GIPC1 human monoclonal antibody was established from a breast cancer patient.…”

“…1, 2, 3, 4, 16, 17, 18, 19, 20, 21, 22, 23, 24 GIPCs are involved in the trafficking of various transmembrane proteins and regulate a variety of cellular processes, such as proliferation, planar cell polarity, cytokinesis and migration. Pathologies associated with the GIPCs, such as hearing loss 11, 12 and cancer, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 are emerging topics in the medical sciences. Here, the functional proteomics, evolutionary genetics, human genetics and cancer biology of the GIPC family members will be reviewed, with a focus on recent advances and future directions.…”

Is ADRM1 a Good Target for Cancer Therapy?

“…The study by Zheng et al [3 ]in this issue of Acta Haematologica further confirms the mechanism by elegantly demonstrating increased nuclear fraction of p65, one of the NF-κB proteins, in the presence of overexpressed ADRM1. Inhibiting ADRM1 has also been shown to downregulate the growth factor GIPC1 and upregulate the tumor suppressors RECK and p53 [4,5]. …”