Poly-(A)-binding protein cytoplasmic 1 gene regulates cell proliferation via TP53 R273H hotspot activation in Japanese patients with common cancer types

Background Mutations in TP53 occur in approximately half of all common cancer types, and play a critical role in tumor progression and metastasis. However, because mutant TP53 can result in both loss and gain of function in cells, complicating the development of drugs that directly target TP53 . We screened for genes whose expression is directly/indirectly increased by specific TP53 mutations that affect cancer progression. Methods We explored potential effector molecules based on differences in gene expression between patients with colorectal (CRC, n = 370), lung (LC, n = 347), and stomach cancers (STC, n = 282) carrying wild-type TP53 , and patients with CRC (n = 902), LC (n = 349), and STC (n = 237) carrying TP53 mutations. Results Frequencies of TP53 mutations in CRC, LC, and STC were 70.9%, 50.1%, and 45.7%, respectively, and the most frequent TP53 missense mutation was TP53- R273H. Comprehensive gene expression analyses comparing patients with TP53 mutations and those with wild-type TP53 identified 24 genes whose expression was significantly increased in TP53 -mutated patients, and 20 genes whose expression was decreased across all three tumor types. Among these genes, poly-(A)-binding protein cytoplasmic 1 ( PABPC1 ) showed significantly increased expression in A549 LC and MCF7 breast cancer cell lines carrying wild-type TP53 transfected with TP53- R273H mutants, but not TP53 -R175H and TP53 -D49H mutants. Furthermore, transient transfection with a plasmid encoding small interfering RNA targeting PABPC1 significantly suppressed the proliferation of HT29 and SW480 colon cancer cell lines harboring the TP53- R273H mutation. Additionally, patients with CRC harboring the TP53 -R273H with high PABPC1 expression had poorer overall survival than those with low PABPC1 expression. Conclusion To our knowledge, this is the first report to demonstrate whether PABPC1 is upregulated by TP53- R273H mutation, suggesting that PABPC1 , which potentially functions as an oncogene, may be an effective therapeutic target for patients with TP53- R273H mutation.