CLINT1 is a subtype-specific biomarker and a downstream effector of p53-R273H in lung adenocarcinoma migration

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma (LUAD) being the most prevalent subtype of non-small cell lung cancer (NSCLC). The p53-R273H mutation, a common gain-of-function mutant, promotes tumor progression. Clathrin interactor 1 (CLINT1) is an adaptor protein involved in vesicular transport, but its role in lung cancer remains unclear. Here, we systematically analyzed CLINT1 expression across 33 cancer types using TIMER, UALCAN, and CPTAC databases. CLINT1 was significantly upregulated in LUAD at both mRNA and protein levels, but not in lung squamous cell carcinoma (LUSC). High CLINT1 expression correlated with poor overall survival and first-progression survival in LUAD patients, but not in LUSC. Gene set enrichment analysis revealed that CLINT1 is associated with type I interferon response and fatty acid catabolic processes. Mechanistically, CLINT1 was identified as a downstream effector of p53-R273H, mediating its pro-migratory effects in LUAD cells. Knockdown of CLINT1 inhibited cell migration and invasion, while overexpression enhanced these phenotypes. Our findings establish CLINT1 as a subtype-specific biomarker and a potential therapeutic target for LUAD, particularly in p53-R273H-mutant tumors.

1. Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, with approximately 1.8 million deaths attributed to it in 2020. In China, lung cancer mortality exhibits pronounced geographical and sex-specific disparities, with particularly unfavorable trends in rural western regions. Metastasis is the primary cause of death in patients with advanced disease. Lung cancer is broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for approximately 85% of all cases. NSCLC is further subdivided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and large cell carcinoma. LUAD is the most prevalent subtype of NSCLC, particularly among women and non-smokers, and represents a major contributor to lung cancer mortality. The pathogenesis of LUAD is closely associated with diverse genetic mutations and epigenetic alterations. Several molecular alterations, such as EGFR mutations, ALK rearrangements, and KRAS mutations, are closely linked to LUAD initiation and progression and have become the basis for targeted therapies.

The p53 protein is a critical tumor suppressor that regulates the cell cycle, maintains genomic stability, and induces apoptosis. TP53 is the most frequently mutated gene in NSCLC, occurring in over 50% of cases overall and in approximately 39% to 46% of adenocarcinomas. Most TP53 mutations occur within the DNA-binding domain, with the R273H mutation standing out as a representative DNA contact mutant and one of the most prevalent variants, accounting for approximately 3.1% of all p53 mutations in human cancers. Notably, the R273H mutation confers unique gain-of-function (GOF) traits, prominently enhancing cell migration, invasion, and metastasis, which are key phenotypes driving LUAD progression. Distinct from other p53 mutants, R273H exerts oncogenic effects by directly binding to cellular proteins and dysregulating cancer-associated transcriptional networks. This renders it a pivotal target for deciphering mutant p53-driven malignant progression in LUAD. Consequently, identifying key molecules associated with the R273H mutation holds significant research and clinical value in both LUAD research and clinical practice.