期刊
MOLECULAR THERAPY
卷 30, 期 4, 页码 1564-1577出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2022.01.003
关键词
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资金
- National Natural Science Foundation of China [82170952, 31970679]
- Shanghai Rising-Star Program [19QA1405000]
- Science and Technology Commission of Shanghai [17ZR1443400, 20Y11903700, 20JC1410100]
- Clinical Research Plan of SHDC [SHDC2020CR4082]
- Shanghai Municipal Health Com-mission [2020040457]
- Innovative Research Team of High-Level Local Universities in Shanghai [SSMU-ZDCX20180901]
- Shanghai Institute of Precision Medicine, Ninth People's Hospital Shanghai Jiao Tong University School of Med-icine [JC201807]
- Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine and College of Stomatology, Shanghai Jiao Tong University [KQYJXK2020]
This study found that the long non-coding RNA IFITM4P is highly expressed in oral squamous cell carcinoma (OSCC), and its overexpression or knockdown can respectively increase or decrease cell proliferation. IFITM4P is involved in regulating the activation of an immunosuppressive program through different mechanisms in the cytoplasm and nucleus, and tumors with high IFITM4P expression show notable therapeutic sensitivity to PD-1 monoclonal antibody (mAb) treatment.
Oral squamous cell carcinoma (OSCC), which is typically preceded by oral leukoplakia (OL), is a common malignancy with poor prognosis. However, the signaling molecules governing this progression remain to be defined. Based on microarray analysis of genes expressed in OL and OSCC samples, we discovered that the long non-coding RNA IFITM4P was highly expressed in OSCC, and ectopic expression or knockdown of IFITM4P resulted in increased or decreased cell proliferation in vitro and in xenografted tumors, respectively. Mechanistically, in the cytoplasm IFITM4P acted as a scaffold to facilitate recruiting SASH1 to bind and phosphorylate TAK1 (Thr187), and in turn to increase the phosphorylation of nuclear factor kappa B (Ser536) and concomitant induction of PD-L1 expression, resulting in activation of an immunosuppressive program that allows OL cells to escape anti-cancer immunity in cytoplasm. In nucleus, IFITM4P reduced Pten transcription by enhancing the binding of KDM5A to the Pten promoter, thereby upregulating PD-L1 in OL cells. Moreover, mice bearing tumors with high IFITM4P expression had notable therapeutic sensitivity to PD-1 monoclonal antibody (mAb) treatment. Collectively, these data demonstrate that IFITM4P may serve as a new therapeutic target in blockage of oral carcinogenesis, and PD-1 mAb can be an effective reagent to treat OSCC.
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