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The relationship between Ki67 and HIF-1 in cancer

Fri, 09/02/2016 - 13:24

Ki67, also known as MKI67, is best known as the leading marker of cellular proliferation. Ki67 is regulated by a balance between synthesis and degradation, and often carries a very short half-life.  First discovered to be located to dividing cells, Ki67 has since been specifically localized to the G1, S, G2 and M phases of mitosis. Soon after, it was discovered that there was a high correlation of Ki67 alongside the p53 (tumor suppressing protein 53), suggesting an implication in cancer. What’s more, the expression of Ki67 is higher in malignant cells versus control cells. With this data, researchers are taking a closer look between the behaviors of Ki67 alongside proliferation in cancer cells.  In particular, the following articles use the Ki67 primary antibody when investigating the role of HIF-1 in different types of cancers.  Hif-1, or hypoxia inducing factor 1, controls our adaptive response to oxygen availability. Depending on our internal or external environments, HIF proteins respond and ultimately affect cellular proliferation, cell survival, immune response, and more.

For starters, Hongxia Hu et al used a Ki67 antibody in their research on HIF-1 and glutamate signaling in cancer cells. To begin, they used HIF-1 and glutamate receptor primary antibodies to show that glutamate receptor signaling stimulates proliferation of hypoxic Hep3B cells. Next, a Ki67 antibody was used in immunohistochemistry on tissue sections of immune compromised mice that had been introduced to Hep3b cells and an AMPA receptor antagonist. The results of this study showed that cellular proliferation of tumor cells decreased in the presence of the AMPA receptor antagonist, which is regulated by the Src family of proteins and ultimately HIF-1. This group also used a HIF-2 alpha antibody and HIF-1 beta antibody in ChIP assays as well. Overall their findings show that HIF-1 activity coordinated the transcription of glutamate transporters that in turn activated cancer cell proliferation, survival and migration.

Another group, Xiang et al, used a Ki67 antibody in their research of targeted therapies for triple negative breast cancer (a very aggressive form of breast cancer with limited treatment options). Interestingly, a hallmark of triple negative breast cancer is the expression of HIF proteins, therefore blocking these factors. Using a Ki67 antibody in immunohistochemistry, this group found that MDA-MB-231 human triple-negative breast cancer cells responded to Ganetespib treatment by showing reduction of tumor growth alongside reduced levels of Ki67 staining in tissue samples. Further testing revealed that the mechanism by which Ganetespib inhibited tumor invasion and metastasis was through inhibition of HIF-1 alpha expression (where HIF-2 alpha antibody levels remained the same). Ultimately, their findings provide promise for Ganetespib to not only slow triple negative breast cancer, but also other disease where HIF1 proteins are responsible for vascular defects (angiogenesis) and more.    

PMID: 24248265
PMID: 25326682
PMID: 25384676

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