Department of Oral Mucosal Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
J Cell Biochem. 2021 Oct;122(10):1302-1312. doi: 10.1002/jcb.29951. Epub 2021 May 10.
Although dysregulation and dysfunction of long noncoding RNAs (lncRNAs) have been implicated in malignant behavior of oral squamous cell carcinoma (OSCC), whether aberrant lncRNAs play a role in the carcinogenesis of oral leukoplakia (OL) as the best-known precursor of OSCC remains undetermined. Differentially expressed lncRNAs in the occurrence and progression of OL were studied by microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We found a novel key lncRNA n386251 that we named LOLA1 (lncRNA oral leukoplakia progressed associated 1) in the OL progression. The results of qRT-PCR revealed that LOLA1 aberrant expression was validated in tissue samples and cell lines from the normal oral mucosa, OL to OSCC. Fluorescent in situ hybridization showed that LOLA1 expression localized predominately at the cytoplasm of Leuk1 cells. Cell function assays showed that LOLA1 significantly influenced cell migration, invasion, and epithelial-mesenchymal transition (EMT) protein expression. Potential mechanism experiments revealed that AKT/GSK-3β signaling was involved in the regulatory mechanism of LOLA1 in OL progression. Remarkably, Kaplan-Meier analysis revealed that LOLA1 overexpression could predict malignant events of OL progression to OSCC. In conclusion, the current study for the first time profiled and validated the key lncRNAs related to OL progression. Importantly, we demonstrated that a novel lncRNA LOLA1 upregulation was associated with OL malignant progression, suggesting LOLA1 may be a predictive biomarker. Moreover, LOLA1 may promote migration, invasion, and EMT process in OL malignant progression via AKT/GSK-3β pathway.
尽管长链非编码 RNA（lncRNA）的失调和功能障碍已被认为与口腔鳞状细胞癌（OSCC）的恶性行为有关，但异常的 lncRNA 是否在口腔白斑（OL）的癌变中发挥作用，OL 是 OSCC 最著名的前体，目前仍不确定。通过微阵列和定量逆转录聚合酶链反应（qRT-PCR）研究了 OL 发生和进展中差异表达的 lncRNA。我们在 OL 进展中发现了一种新型关键 lncRNA n386251，我们将其命名为 LOLA1（lncRNA 口腔白斑进展相关 1）。qRT-PCR 结果验证了 LOLA1 在组织样本和来自正常口腔黏膜、OL 到 OSCC 的细胞系中的异常表达。荧光原位杂交显示 LOLA1 表达主要定位于 Leuk1 细胞的细胞质中。细胞功能测定表明，LOLA1 显著影响细胞迁移、侵袭和上皮-间充质转化（EMT）蛋白表达。潜在的机制实验表明，AKT/GSK-3β 信号通路参与了 LOLA1 在 OL 进展中的调节机制。值得注意的是，Kaplan-Meier 分析显示 LOLA1 过表达可预测 OL 进展为 OSCC 的恶性事件。总之，本研究首次对与 OL 进展相关的关键 lncRNA 进行了分析和验证。重要的是，我们证明了新型 lncRNA LOLA1 的上调与 OL 的恶性进展相关，表明 LOLA1 可能是一种预测性生物标志物。此外，LOLA1 可能通过 AKT/GSK-3β 通路促进 OL 恶性进展中的迁移、侵袭和 EMT 过程。
