EFFECT OF CD320 KO ON PROLIFERATION OF LUNG CANCER CELLS

Abstract

Mutations in the TP53 tumor suppressor gene are the most common genetic alteration found in human cancers, identified in almost half of human malignancies. Other tumor suppressors (e.g., RB, APC, and BRCA1) are usually inactivated through frameshift or nonsense mutations; however, the majority of TP53 mutations (approximately 80%) are missense mutations resulting in a p53 protein that can exhibit altered and potentially deleterious functions. Some reports have described mutant p53 variants that can act in concert with cancer progression. These gain-of-function mutants, like R273H and M246I, turn p53 from “a brake to an accelerator” – no longer stopping tumors, but stepping on the gas, especially in non-small cell lung cancer (NSCLC), where they are associated with aggressive phenotypes and resistance to therapy. CD320, a receptor for the uptake of cobalamin (vitamin B12) by binding transcobalamin, is upregulated in rapidly proliferating cells, including various cancers. Its role in cancer proliferation makes it a promising target for therapeutic intervention. Recent unpublished work from Dr. Larisa Lezina’s lab has shown that TP53 GOF mutations lead to CD320 upregulation in non-small cell lung cancer (NSCLC) cells. However, this raises the critical questions: how does mutant p53 regulate CD320 transcription or translation? To investigate this, the study will generate CRISPR/Cas9-based CD320 knockout NSCLC cell lines to analyze the transcriptional and translational consequences of p53 GOF mutations on CD320 expression. From this work, we hope to clarify the oncogenic relationship between mutant p53 and CD320, and provide molecular bases that may lead to new, specific targeting therapies in cancers with such activating mutations.