Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma
Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma
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DOI：
10.3390/cancers11121854
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Shu, Chih-Wen
中科院分区：
文献类型：
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作者：
Liu, Pei-Feng;Chen, Hung-Chih;Shu, Chih-Wen
由于生物标志物和治疗靶点的有限性，口腔鳞状细胞癌（OSCC）是全球癌症死亡的主要原因之一。自噬相关蛋白酶4 B（Autophagy Related Protein 4 B，ATG 4 B）是自噬机制中的一种重要蛋白酶，其丝氨酸383/392位的磷酸化增强了其蛋白水解活性。ATG 4 B的表达和激活对于癌细胞的增殖和侵袭是至关重要的。然而，ATG 4 B和磷酸化Ser 383/392-ATG 4 B与口腔鳞癌的临床相关性仍然未知，特别是在颊粘膜鳞癌（BMSCC）和舌鳞癌（TSCC）中。结果发现，与癌旁正常组织相比，BMSCC和TSCC组织中ATG 4 B和phospho-Ser 383/392-ATG 4 B蛋白表达水平均显著升高，其中BMSCC组179例，TSCC组249例。高蛋白水平的ATG 4 B与OSCC患者的疾病特异性生存率（DSS）显著相关，特别是在晚期肿瘤患者中。相比之下，磷酸化Ser 383/392-ATG 4 B表达与TSCC患者的无病生存率（DFS）相关。ATG 4 B蛋白表达与磷酸化Ser 383/392-ATG 4 B表达呈正相关。然而，ATG 4 B和磷酸化Ser 383/392-ATG 4 B的高共表达水平仅与TSCC患者的DFS差相关，而它们与BMSCC和TSCC患者的DSS无显著相关性。此外，用反义寡核苷酸（阿索）或小干扰RNA（siRNA）沉默ATG 4 B减少了TW2.6和SAS口腔癌细胞的细胞增殖。此外，ATG 4 B的敲低降低了口腔癌细胞的细胞迁移和侵袭。综上所述，这些发现表明ATG 4 B可能是OSCC诊断/预后的生物标志物和OSCC患者的潜在治疗靶点。
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 428 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.