LINCRNA00273 promotes cancer metastasis and its G-Quadruplex promoter can serve as a novel target to inhibit cancer invasiveness

// Samarjit Jana 2, * , Jagannath Jana 1, * , Kartick Patra 2 , Soma Mondal 1 , Jyotsna Bhat 1 , Arnab Sarkar 2 , Pallabi Sengupta 1 , Anindya Biswas 3 , Meghomukta Mukherjee 1 , Satya Prakash Tripathi 5 , Rahul Gangwal 5 , Joyita Hazra 6 , Abhay T. Sangamwar 7 Gopeswar Mukherjee 4 , Shamee Bhattacharjee 2 , Deba Prasad Mandal 2 and Subhrangsu Chatterjee 1 1 Department of Biophysics, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India 2 Department of Zoology, West Bengal State University, Malikapur, Kolkata 700126, India 3 Department of Biochemistry, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi, Kolkata 700054, India 4 Barasat Cancer Research and Welfare Centre, Barasat, Kolkata 700124, India 5 Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Punjab 160062, India 6 Department of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VIIM, Kankurgachi Kolkata 700054, India 7 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S. Nagar, Punjab 160062, India * These authors have contributed equally to this work Correspondence to: Subhrangsu Chatterjee, email: subhro_c@jcbose.ac.in Deba Prasad Mandal, email: dpmandal1972@gmail.com Shamee Bhattacharjee, email: shamee1405@gmail.com Keywords: long non coding intergenic RNA; cancer metastasis; G-quadruplex; epithelial to mesenchymal transition Received: September 20, 2016      Accepted: September 13, 2017      Published: November 17, 2017 ABSTRACT Discovery of anti-metastatic drugs is of immense clinical significance as metastasis is responsible for 90% of all cancer deaths. Here we report the inhibitory effect of a bis schiff base (M2) on cancer cell migration and invasion in vitro and in vivo . M2 has shown good solubility and permeability across the intestinal cell wall and hence can be classified as BCS (Biopharmaceutical classification system) class I. Microarray studies identified a long non coding intergenic RNA, LINC00273 as a novel molecular target of M2. We report that LINC00273 harbors a unique (4n-1) parallel G-Quadruplex structure in its promoter as validated by DMS footprint. M2 is proposed to stabilize this G-quadruplex structure resulting in the down-regulation of LINC00273 expression. Dual Luciferase reporter assay also suggests inhibition of LINC00273 promoter activity by M2. Involvement of this linc in metastasis is proven by siRNA and shRNA mediated knock down of LINC00273 in vitro and in vivo in nude mice which significantly decelerates cancer cell migration and invasion and also makes the cells unresponsive to TGF-β’s pro-metastatic effects. Furthermore, the real time expression of LINC00273 in thirty seven human clinical samples is found to be positively correlated with the histopathological staging of metastasis.