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Published on: January 12, 2020
Suppression of GNAI2 message in ovarian cancer
John R Raymond, Kathryn M Appleton, Jennifer Y Pierce
1Department of Drug Discovery and Biomedical Sciences, College of Pharmacy Medical University of South Carolina, 280 Calhoun St, QF415, Charleston, SC 29425, USA. petersy@musc.edu.
Background:
Understanding the integration of hormone signaling and how it impacts oncogenesis is critical for improved cancer treatments. Here we elucidate GNAI2 message alterations in ovarian cancer (OvCa). GNAI2 is a heterotrimeric G protein which couples cell surface hormone receptors to intracellular enzymes, and is best characterized for its direct role in regulating cAMP response element-binding protein (CREB) function by decreasing intracellular cAMP through inhibiting adenylyl cyclase.
Methods:
We probed the Origene human OvCa array for the presence of polymorphisms and gene expression alterations of GNAI2 using directing sequencing and qPCR. These data were supported by database mining of the [NCBI NIH GSE:6008, GSE:14764, GSE:29450, GDS:4066, GDS:3297, GSE:32474, and GSE:2003] datasets.
Results:
No significant polymorphisms were found, including an absence of the gip2 oncogene. However, 85.9% of (506 of 589) OvCa patients had decreased GNAI2 message. Further characterization demonstrated that the GNAI2 message was on average decreased 54% and maximally decreased by 2.8 fold in clear cell carcinoma. GNAI2 message decreased in early stage cancer while message was increased compared to normal in advanced cancers. The changes in GNAI2 also correlated to deregulation of CREB, Fos, Myc, cyclins, Arf, the transition from estrogen dependence to independence, and metastatic potential.
Conclusion:
These data strongly implicate GNAI2 as a critical regulator of oncogenesis and an upstream driver of cancer progression in OvCa.
Insights
Decreased GNAI2 gene expression is prevalent in ovarian cancer (OvCa), correlating with cancer progression and deregulation of key oncogenic pathways. This highlights GNAI2 as a potential therapeutic target in OvCa.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hormone signaling significantly impacts oncogenesis, necessitating a deeper understanding for improved cancer therapies.
- GNAI2, a heterotrimeric G protein, plays a critical role in regulating intracellular signaling pathways, including cAMP levels and CREB function.
- Alterations in GNAI2 expression are investigated in the context of ovarian cancer (OvCa) development and progression.
Purpose of the Study:
- To investigate GNAI2 message alterations, including polymorphisms and gene expression levels, in ovarian cancer patients.
- To determine the correlation between GNAI2 expression changes and key oncogenic pathways and clinical parameters in OvCa.
Main Methods:
- Utilized direct sequencing and quantitative PCR (qPCR) to analyze GNAI2 in an ovarian cancer array.
- Performed extensive database mining of publicly available datasets (NCBI GEO) to support findings.
Main Results:
- No significant GNAI2 polymorphisms were identified; however, 85.9% of OvCa patients exhibited decreased GNAI2 message.
- GNAI2 message was significantly reduced in clear cell carcinoma and decreased in early-stage OvCa, but increased in advanced stages.
- Decreased GNAI2 expression correlated with the deregulation of CREB, Fos, Myc, cyclins, Arf, estrogen dependence, and metastatic potential.
Conclusions:
- GNAI2 is implicated as a critical regulator in ovarian cancer oncogenesis.
- Altered GNAI2 expression acts as an upstream driver of cancer progression in OvCa.
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