Bio Patrika interviews Mrs. Singh on her thoughts about “miRNA replacement based cancer therapies”

Mrs. Anukriti Singh’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Mrs. Singh is currently a PhD student in the lab of Prof. Bushra Ateeq (Shanti Swarup Bhatnagar Prize 2020 for Medical Sciences) at the department of Biological Sciences & Bioengineering, Indian Institute of Technology, Kanpur. She published a paper titled “Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma” as a first author in Neoplasia journal (2020).

How would you explain your paper’s key results to the non-scientific community?

Angiotensin Receptor Type 1 or AGTR1 is a gene that regulates blood pressure in the normal human body but when this gene produces an excess of protein (overexpression), then it acts as an “oncogene” or a cancer-causing gene which drives cancer in several organs including breast and brain. However, the mechanism underlying the overexpression of AGTR1 in cancer was still unknown. In our study, we deciphered this mechanism wherein AGTR1 driven cancers are caused by activation of a signaling pathway in glioblastoma (GBM) and breast cancer (BCa). A signaling pathway is formed by the activation of a receptor by a molecule called a ligand leading to a cascade of signals that further activate other molecules. We found that the ligand Angiotensin II mediates stimulation of AGTR1 receptor and leads to activation of the Nuclear Factor-κB (NF-κB) pathway which further leads to activation of another cancer-causing gene named C-X-C chemokine receptor type 4 (CXCR4) and upregulates AGTR1 via a feedback loop. Hence, the AGTR1/ NF-κB / CXCR4 signaling axis mediates the overexpression of AGTR1 in GBM and BCa. We also show that a micro RNA named microRNA 155 (miR-155) abrogates this signaling axis and hence the AGTR1 mediated oncogenesis. MicroRNA is a small RNA of 22 nucleotides that binds to the target messenger RNA and inhibits it from making proteins. We show that miR-155 along with inhibiting this signaling axis also abrogates “angiogenesis” or new blood vessel formation in the chicken model as well as reduces oncogenic properties such as proliferation and invasion in GBM and BCa cells. Moreover, our most intriguing finding was observed when miR-155 overexpressed GBM cells failed to grow tumors in mice on implantation, whereas the control GBM cells formed sizeable tumors. We also noted that pharmacological inhibitors of the NF-κB pathway namely IKK inhibitors also abrogate the AGTR1/ NF-κB / CXCR4 signaling axis. Therefore, our research opens avenues for the potential use of miRNA replacement therapy and IKK inhibitors for the treatment of AGTR1 positive malignancies.

Figure 1. Scheme representing AGTR1 signaling in breast cancer and glioblastoma and its inhibition by miR-155.

“We propose a therapeutic intervention for AGTR1 positive subset of cancer patients where we suggest miRNA replacement therapy and the use of IKK inhibitors for the treatment of AGTR1 positive GBM and BCa patients.”

What are the possible consequences of these findings for your research area?

Glioblastoma (GBM) is a deadly disease with average patient survival of fifteen months with treatment and three months without treatment. On the other hand, breast cancer (BCa) is first in terms of incidence and mortality, both in India and worldwide amongst women. Our research proposes a therapeutic intervention for a subset of patients of both these cancers, where we propose miRNA replacement therapy and the use of IKK inhibitors for the treatment of AGTR1 positive GBM and BCa patients. Where different strategies of delivering miRNAs are being currently developed and are in clinical trials for other diseases including ones focusing on delivery across the blood-brain barrier. The use of IKK inhibitors is also in clinical trials for different diseases. Therefore, both these therapeutic measures are translatable to clinics in the future.

What was the exciting moment (eureka moment) during your research?

“To raise new questions, new possibilities, to regard old problems from a new angle, requires creative imagination and marks real advance in science” – Albert Einstein.

Though the whole research journey has been exciting but building a project block by block as you unearth new pieces of information experimentally is the best part. However, there were two specific highlights or exciting moments in this project. The first was the result of the mice experiment which was of utmost intriguing nature. Where control GBM cells formed sizeable tumors when implanted in mice, the GBM cells overexpressed with miR-155 failed to grow tumors in mice on implantation. The difference was very stark and discernable by eye, which made us excited to pursue the signaling pathways that might be working towards this tumor repressive function. This led to the second very exciting and step by step discovery of AGTR1/ NF-κB / CXCR4 signaling axis behind the AGTR1 mediated oncogenesis. Every piece of data that unraveled this axis bit by bit was an exciting moment.

What do you hope to do next?

The next step should be working on the delivery of these miRNAs in vivo and further taking the miRNA replacement therapy to the clinical trial stage.

Where do you seek scientific inspiration?

Since the very beginning of my scientific career, I have been interested in translational research and worked in the field of disease research which brought me in contact with patients. As I interacted with patients, witnessed difficult circumstances and emotions, it became clear to me that I needed to work in the direction of helping the patients somehow. And the best way to do so is to make my earnest contribution to the field of disease research. My inspiration lies in the fact that I want to make a difference, no matter how small, to the lives of the suffering patients.

How do you intend to help Indian science improve?

Indian science has come a long way but much of research done in labs is not translated to clinics. I intend to make my contribution to Indian science by bringing the research from “bench to bedside” that is working in direction of taking the research to clinics for the benefit of patients.

Reference

Singh A, Srivastava N, Yadav A, Ateeq B. Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma. Neoplasia. 2020;22(10):497-510.

Email: anukriti.aiims@gmail.com, anukriti@iitk.ac.in

Learn more about Dr. Bushra Ateeq’s lab research interests http://home.iitk.ac.in/~bushra/

Read more about findings on scisoup by Ratnesh Thakur.

Watch Anukriti’s video explaining her findings https://youtu.be/uLTCCinsK24.

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