Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
MRC-Holland, Willem Schoutenstraat, the Netherlands.
Cancer Res. 2015 Apr 1;75(7):1287-97. doi: 10.1158/0008-5472.CAN-14-2444.
Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis.
正确的顶端-基底极性和细胞间黏附对于正常上皮的适当发育至关重要。在这里，我们研究了细胞极性调节剂 PARD3 对肺鳞状细胞癌（LSCC）发展的贡献。在检查的 8%的 LSCC 中发现了肿瘤特异性的 PARD3 改变，这使得 PARD3 成为这种恶性肿瘤中最常见的肿瘤抑制基因之一。大多数 PAR3 突变蛋白显示出介导紧密连接和基于肌动蛋白的突起形成、与非典型蛋白激酶 C 结合、激活 RAC1 和在细胞汇合时激活 STAT3 的能力相对降低。因此，PARD3 的改变阻止了相邻细胞之间的接触以及随后的下游信号传导。值得注意的是，体内重建 PAR3 活性可降低肿瘤侵袭性和转移特性。我们的研究结果将 PARD3 定义为 LSCC 中反复失活的细胞极性调节剂，它影响肿瘤的侵袭性和转移。
