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

Samarjit Jana,Jagannath Jana,Gopeswar Mukherjee,Joyita Hazra,Shamee Bhattacharjee,Satya Prakash Tripathi,Abhay T Sangamwar,Meghomukta Mukherjee,Jyotsna Bhat,Kartick Patra,Rahul Gangwal,Soma Mondal,Anindya Biswas,Subhrangsu Chatterjee,Arnab Sarkar,Deba Prasad Mandal,Pallabi Sengupta

doi:10.18632/oncotarget.22622

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.

Highlights

Despite significant advances in cancer therapy, cancer still continues to be the leading cause of mortality worldwide
The antineoplastic effect of various doses of M2 was investigated in vivo in three transplantable tumor models viz., Sarcoma-180 (S-180), Ehrlich ascites carcinoma (EAC) and B-16 melanoma [Supplementary Figure 1 (II) – (V)] & [Supplementary Figure 2 (I)]
The failure of cancer therapies to treat malignant tumors has intensified the need for anti-metastatic drugs

Summary

Introduction

Despite significant advances in cancer therapy, cancer still continues to be the leading cause of mortality worldwide. Till date, success in cancer treatment has been largely facilitated by early stage diagnosis and controlling localized cancer or primary tumor growth This limited clinical success is further attenuated by the broad spectrum side effects of all the major anticancer drugs. Integrin inhibitors (Abegrin, Vitaxin), Matrix Metallo Protease (MMP) inhibitors, Transforming Growth Factor β (TGFβ) inhibitors etc are being developed as a promising attempt to block invasion Either these inhibitors have not been efficacious in clinical trials [5] or have been found to cause an increase of tumor progression [8] or are too ubiquitous and non specific targets, which may cause intolerable side effects in combination with standard therapies [9]. This illustrates an urgent need to identify specific molecular ‘kingpins’ during the course of metastasis and to develop agents which would target those molecules to control cancer spread

Methods

Results

Conclusion