New study suggests that the use of miR-155 replacement therapy or pharmacological inhibitors of IKK complex might be beneficial for the treatment of AGTR1-positive glioblastoma and breast cancer patients.
OCT 16, 2020 | BY RATNESHWAR THAKUR
Glioblastoma (GBM) is the most common form of malignant brain cancer that usually results in death within the first 15 months of diagnosis. Researchers believe that understanding the oncogenic role of genes that might function as drivers for GBM may help discover effective therapeutic interventions for the benefit of GBM patients.
The researchers say Angiotensin II Receptor Type 1 (AGTR1) is a gene responsible for regulating the blood pressure. But, when AGTR1 generates too much or “overexpression” of its protein, AGTR1 drives cancer in a variety of organs such as the cervix, ovary, prostate, and breast but the underlying mechanism involved in AGTR1 up regulation was not known thus far.
Now in a new study, Prof. Bushra Ateeq and her team at Indian Institute of Technology Kanpur- has unravelled the mechanism underlying elevated levels of AGTR1 in GBM and breast cancer (BCa), and suggests possible therapeutic approaches to target it in AGTR1-positive patients of both GBM and BCa. The results of this study have been published in the journal ‘Neoplasia’.
To confirm if AGTR1 was indeed the culprit, investigators in Bushra’s lab “silenced” or decreased AGTR1 protein levels in GBM and BCa cell lines. Interestingly, as per their expectation they observed reduction in the “oncogenic” or cancer-causing properties of these engineered cell lines.
In this study, Bushra’s team found that a microRNA named, miR-155 is involved in controlling the levels of AGTR1 in these cancers. They decided to introduce and test the effect of miR-155 in the AGTR1-positive GBM and BCa cell lines. To their surprise when the miR-155 level in the cancer cell lines was increased, AGTR1 levels decreased along with many cancerous properties, such as cell proliferation, invasion, angiogenesis, EMT, and stemness.
Importantly, when miR-155 overexpressing GBM cells were implanted in the mice, they failed to form tumors, whereas mice implanted with control GBM cells developed large tumors. Moreover, in a chicken embryo experiment, miR-155 overexpressing GBM cells failed to form new blood vessels compared to the chick embryos implanted with control cells.
Furthermore, Bushra’s team also unravelled that interaction between AGTR1, NF-κB and CXCR4, which is crucial for AGTR1 protein mediated oncogenic effects. “We could successfully disrupt this signalling axis by using either miR-155 or I kappa B kinase (IKK) inhibitor, which abrogates oncogenesis in GBM and breast cancer, says Anukriti Singh, the lead author in this study.
These findings suggest that the use of miR-155 replacement therapy or pharmacological inhibitors of IKK complex might be beneficial for the treatment of AGTR1-positive glioblastoma and breast cancer patients.
Investigating members were Anukriti Singh, Nidhi Srivastava, Anjali Yadav and Bushra Ateeq. The study was financially supported by Department of Biotechnology, Ministry of Science and Technology, Government of India.
Journal Reference:
Targeting AGTR1/NF-jB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma
