PRRX1 Regulates Cellular Phenotype Plasticity and Dormancy of Head and Neck Squamous Cell Carcinoma Through miR-642b-3p
PRRX1 Regulates Cellular Phenotype Plasticity and Dormancy of Head and Neck Squamous Cell Carcinoma Through miR-642b-3p
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PRRX1通过miR-642b-3p调节头颈鳞状细胞癌的细胞表型可塑性和休眠
DOI：
10.1016/j.neo.2018.12.001
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Liang, Xin-hua
中科院分区：
文献类型：
--
作者：
Jiang, Jian;Zheng, Min;Liang, Xin-hua
背景：休眠是癌细胞的一个特征，使患者在转移和复发前保持无症状状态，这与包括头颈部鳞状细胞癌（HNSCC）在内的癌症患者的生存率密切相关。PRRX1先前在不同类型的人类癌症中参与上皮-间质转化（EMT）过程的侵袭和转移。然而，PRRX1是否能够调节癌症休眠及其再激活，从而导致HNSCC细胞的迁移和侵袭尚不清楚。本研究的目的是确定PRRX1在HNSCC细胞表型可塑性和癌症休眠中的作用及其与HNSCC中mirna的关联。方法：采用免疫组化染色法检测原发性HNSCC和转移淋巴结中PRRX1的表达。同时，我们在体外和体内研究了PRRX1在HNSCC细胞表型可塑性和癌症休眠中的作用及其与miR-642b-3p和EMT的关系。结果：与转移性淋巴结相比，HNSCC侵袭前PRRX1明显升高，这种转换过程伴随着细胞表型可塑性和细胞休眠激活。在HNSCC细胞系中，PRRX1积极促进已知EMT诱导剂的表达，并与活化的tgf - β 1协同参与EMT和HNSCC细胞的迁移和侵袭。然后，我们发现在prrx1过表达的细胞中，miR-642b-3p是下调最明显的miRNAs之一，过表达miR-642b-3p可以显著减少细胞的迁移和侵袭，增加细胞的增殖和凋亡。miR-642b-3p恢复通过tgf - β 2和p38逆转prrx1诱导的HNSCC细胞休眠和EMT。最后，我们证明了在异种移植HNSCC模型中，PRRX1过表达与miR-642b-3p下调以及tgf - β 2和p38上调密切相关。结论：我们的研究结果表明，PRRX1可能是HNSCC细胞表型可塑性和肿瘤休眠的主要驱动力之一。因此，我们可以提出一种可能性，即EMT可能有助于使癌细胞保持休眠状态，而间充质-上皮转化可能会使HNSCC的休眠状态恢复。
BACKGROUND: Dormancy is one characteristic of cancer cells to make patients remain asymptomatic before metastasis and relapse, which is closely related to the survival rate of cancer patients, including head and neck squamous cell carcinoma (HNSCC). PRRX1 has previously been implicated in the invasion and metastasis of the epithelial-mesenchymal transition (EMT) process in different types of human carcinoma. However, whether PRRX1 can regulate cancer dormancy and its reactivation, leading to the migration and invasion of HNSCC cells, remains elusive. The aim of this study was to determine the role of PRRX1 in cellular phenotype plasticity and cancer dormancy of HNSCC cells and its association with miRNAs in HNSCC. METHODS: The expression of PRRX1 was detected by immunohistochemical staining in primary HNSCC samples and the metastatic lymph nodes. Meanwhile, the role of PRRX1 and its relationship with miR-642b-3p and EMT in cellular phenotype plasticity and cancer dormancy of HNSCC were investigated in vitro and in vivo. RESULTS: PRRX1 was significantly higher at the invasive front of HNSCC samples compared with the metastatic lymph nodes, and such switch process was accompanied by the cellular phenotype plasticity and cell dormancy activation. In HNSCC cell lines, PRRX1 positively promoted the expression of known EMT inducers and cooperated with activated TGF-beta 1 to contribute to EMT and migration and invasion of HNSCC cells. Then, we found that overexpression of miR-642b-3p, one of the most significantly downregulated miRNAs in PRRX1-overexpressed cells, significantly reduced the migration and invasion, and increased cell proliferation and apoptosis. And miR-642b-3p restoration reversed PRRX1-induced cell dormancy and EMT of HNSCC cells through TGF-beta 2 and p38. Finally, we demonstrated that overexpressed PRRX1 was closely correlated with miR-642b-3p downregulation and the upregulation of TGF-beta 2 and p38 in a xenograft model of HNSCC. CONCLUSIONS: Our findings showed that PRRX1 may be one of the main driving forces for the cellular phenotype plasticity and tumor dormancy of HNSCC. Therefore, we can raise the possibility that EMT may help to keep cancer cell in dormant state and mesenchymal-epithelial transition may resurge dormancy in HNSCC.