Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.

Development and Validation of Autophagy-Related Gene Signature and Nomogram for Predicting Survival in Oral Squamous Cell Carcinoma

“…found the co-expression of higher MAP1LC3B and SQSTM1 was significantly associated with poor disease-specific survival and disease-free survival in OSCC patients ( 23 ). In addition, another tissue microarray analysis suggested that ATG4B, an autophagy related protease, could be a potential biomarker for diagnosis and prognosis for OSCC ( 24 ). To date, studies using large-scale expression patterns of ARGs to screen and develop molecular biomarkers and prognostic gene signature for OSCC are still lacking.…”

UBE2C is a Potential Biomarker for Tumorigenesis and Prognosis in Tongue Squamous Cell Carcinoma

“…More than 90% of oral cancers are oral squamous cell carcinoma (OSCC) which is typically observed on the tongue, buccal mucosa and lips [1]. Cigarette smoking, alcohol drinking, betel quid chewing, chronic periodontitis [2] and viral infections [3] are major risk factors contributing to the incidence of OSCC.…”

Autophagy modulation as a potential targeted cancer therapy: From drug repurposing to new drug development

“…ATG4B activity is required for cell cycle progression 34 and the protein levels of ATG4B and phosphorylated ATG4B (S383/392) is highly associated with tumor progression in cancer patients 35,36 . Thus, ATG4B inhibitor is expected to have suppressive effects in cancer cells.…”