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D. Banerjee, S. Molina, D. Takemoto; Cx46, a Hypoxia Specific Lens Gap Junction Protein Which Protects Tumors From Hypoxia. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1695.
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Normal tissues do not survive under hypoxia. The exceptions are lens of the eye (naturally hypoxic) and malignant tumors (adaptive hypoxic) prior to ascularization. Connexin 46 (Cx46) is a novel gap junction protein that appears during lens fiber formation, inside the hypoxic enter of the lens. We have found that tumors such as breast tumor and retinoblastoma cells Y79 also express Cx46.The purpose of the study is to determine if Cx46 protein protects malignant tumors, such as breast tumors or retinoblastoma, and lens from hypoxia.
Expression of Cx46 in solid breast tumor tissue and retinoblastoma cells (Y79) were verified by immunoblot and immunohistochemistry. To verify that Cx46 protects cells from hypoxia ,(a) neuronal N2A cells over-expressing Cx46 (b) human lens epithelial cell (HLEC), and (c) breast cancer cell line MCF-7 ,with Cx46 downregulated by siRNA, were incubatedunder hypoxic condition (1% O2) and cell viability was assessed .To determine if down-regulation of Cx46 eiduces breast cancer tumors in vivo , a tumor xenograftmodel was used where mice were inoculated with 17-Beta-estradiol and injected with 107 breast cancer MCF-7 cells to develop breast tumor. Mice with tumor xenografts were injected with Cx46 siRNA for up to 10 days with injection every other day.
The Cx46 was upregulated in response to hypoxia in lens epithelial NN 1003A cells. Breast cancer cells MCF-7 and retinoblastoma cells Y79 both expressed high level of Cx46 and survived under hypoxic conditions.N2A cells with Cx46 were more resistant to death caused by hypoxia than N2A cells with no Cx46.The downregulation of Cx46 by siRNA in HLEC and MCF-7 cell line made them vulnerable to hypoxia induced cell death. In vivo studies showed that the tumor growth was arrested in mice injected with siRNA only against Cx46.
Cx46 plays an important role to protect solid tumors and lens from hypoxia. The above work is innovative and important as it is the first to compare a naturally hypoxic tissue, the lens, with a diseased hypoxic tissue, breast tumor or retinoblastoma tissue, for their survival strategies involving a novel gap junction protein connexin 46. Results clearly demonstrate a novel role for Cx46 in protection from hypoxia and a potential target for drug design and therapy.
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