Molecular mechanism of prostate cancer subtype unravelled


The molecular mechanism and pathobiology of SPINK1­positive prostate cancer subtype, the second most recurrent and aggressive in nature, that affects about 15% of patients has been finally nravelled. The study was done by a multi­institutional team led by Prof. Bushra Ateeq from the Department of Biological Sciences and Bioengineering at Indian Institute of Technology (IIT) Kanpur. The SPINK1­positive prostate cancer subtype derives its name from the excess amount of SPINK1 oncogene found in the cancer cells. Excess production of SPINK1 gene responsible for tumour and metastasis is not restricted to prostate cancer alone but also seen in colorectal, lung, pancreatic, breast and ovarian cancers. The insights gained in this study might therefore help in the treatment and disease management of several SPINK1­positive malignancies. In addition to excess amount of the SPINK1 oncogene, the researchers found that most cancer cells belonging to this subtype also have more than normal amount of a particular protein called EZH2. Also, the levels of two microRNAs (miRNA­338­5p and miRNA­421) produced in SPINK1­ positive cancer cells were much less. “We found that the increased levels of EZH2 protein triggers the reduction in the synthesis of these two microRNAs in SPINK1­positive canincreased, the SPINK1 level reduced and there were marked changes in the oncogenic properties — the cell proliferation and invasion reduced. “The observations made using SPINK1­positive cell lines were validated in chicken embryos and mouse models,” says Anjali Yadav from the Department of Biological Sciences and Bioengineering at IIT Kanpur and one of the first authors of a paper published in Clinical Cancer Research. In both chicken embryo and mouse model experiments, the SPINK1­positive prostate cancer cells were modified by introducing the microRNAs and were tested for tumour growth and metastasis. “Tumour was found growing aggressively in mice of the control group but significantly reduced in size in the microRNA overexpressing group,” says Vipul Bhatia from IIT Kanpur and the other first author of the paper. “A significant reduction in tumour growth was also observed in chicken embryos that were implanted with microRNA­modified prostate cancer cells.” Metastasis was also significantly reduced in both the lungs and bone marrow of mice implanted with microRNA­modified prostate cancer cells. But  etastasis results were a little different in the case of chicken. While metastasis was less in the lungs, but both control and microRNA modified cancer cells failed to metastasise in the liver. The researchers tested the effectiveness of epigenetic drugs to restore the levels of the microRNAs and reduce the expression of the SPINK1 gene using SPINK1­positive cancer cell lines that did not have the two microRNAs. “These drugs could restore the expression of the two microRNAs leading to a reduction in the SPINK1 expression. We could abrogate the SPINK1­mediated oncogenicity in terms of cell­cycle progression, stemness and drug resistance,” says Prof. Ateeq. “We could see similar effects when we replenished the SPINK1­positive cancer cell lines with synthetic microRNAs.” “We will soon start studying the role of other RNA species which don’t code for proteins but play an important role in SPINK1 gene regulation. We are also looking at other genetic aberrations that play an oncogenic role in the SPINK1­positive subtype,” says Prof. Ateeq

Carbon microneedles: Low­cost,
painless injections

completed his post­doctoral research from the institute. He is one of the corresponding authors of the work published in Nature Microsystems & Nanoengineering. The needles were arranged in a patch (10 X10) and tested for drug delivery. The patch was attached to a 5 ml syringe and flow rate studied. They found the flow corresponds to the inlet pressure suggesting that drug delivery can be controlled by maTiny needles less than 1 mm in size have been developed by researchers from Indian Institute of Technology (IIT) Kharagpur. When arranged on a patch, the tiny hollow icroneedles can be used for painless drug delivery. Last year, the team had developed microneedles from a widely used photosensitive polymer (SU­8). Since the needles were not hard enough and biocompatible, they modified it using a simple process of extreme heating or pyrolysis. This produced glassy carbon needles which were almost 300 times stronger than the original ones. Since it was made of carbon it was also biocompatible. Heating removed most of the nitrogen and oxygen in the polymer and the needle were solely made of carbon. The needles showed no toxicity when tested on mice models, says Prof. Bidhan Pramanick who naging the pressure. Drug delivery “We are now working on developing a drug reservoir and micropump which can be attached to the patch forcontrolled drug delivery. Just like a band­aid, we can fabricate a dia­aid that can be used by diabetic patients for painless insulin administration,” says Tarun Kanti Bhattacharyya from the Department of Electronics and Electrical Communication Engineering at the Institute and one of the corresponding authors of the work. “Though we cannot bring down the cost of insulin, this patch can reduce the device cost by almost 50%.” When a needle is inserted into the skin, it experiences resistance from the skin. A good needle should be able to overcome the forces to penetrate the skin. Using compression and bending tests, the researchers found that the needles did not break or bend when force was applied. The patch was tested on mouse models and even after 15 insertions, the patch and needles remained intact. “We found that the new carbon microneedles overcamethe resistive forces of our skin and was able to successfully pierce the skin. And as the needles are only 400 micrometer long, it will be completely painless,” says Richa Mishra, PhD scholar at the institute and first author of the work/




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