Executive Summary : | The KSRP, a single-stranded RNA binding protein, has been identified as a regulator of myogenesis and has been shown to regulate mRNA stability and translation of inflammatory mRNAs. It has also been shown to play a multifaceted role in cancer, including posttranscriptional mRNA decay and miRNA biogenesis. A KSRP binding small molecule inhibitor has been shown to inhibit colorectal cancer invasion by suppressing non-canonical oncogenic signaling mediated by the EGFR receptor ErbB4. KSRP expression is upregulated in various cancers, including lung and colon cancer. Several targets of KSRP, known regulators of EGF receptor signaling, have been identified, suggesting a crosstalk between KSRP and EGFR signaling. EREG/Epiregulin, an EGFR ligand, is a sought-after target for antitumor therapy. The study aims to investigate the crosstalk between pro-oncogenic KSRP and EGFR signaling using various methods, including RNA-IP, RT-qPCR, Actinomycin D chase experiments, reporter assays, EREG/AREG/TGFA/IL-6 ELISAs, and polysome-profiling. The study will also use a lung cancer/fibroblast co-culture model to investigate the role of KSRP in EREG secretion, CAF activation, and cancer proliferation. The study will also generate loss of function models of KSRP using CRISPR/Cas9 technology in BRAF-mutated, EGFR-mutated, and normal cell lines. Understanding the molecular interplay between KSRP and EGF-related genes will help define specific regimes for anti-tumor intervention. |