CD271 is a negative prognostic factor and essential for cell proliferation in lung squamous cell carcinoma
CD271 is a negative prognostic factor and essential for cell proliferation in lung squamous cell carcinoma
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DOI：
10.1038/s41374-019-0246-5
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发表时间：
2019-09-01
影响因子：
5
通讯作者：
Tamai, Keiichi
中科院分区：
文献类型：
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作者：
Mochizuki, Mai;Nakamura, Mao;Tamai, Keiichi
鳞状细胞癌是肺癌的一种主要类型。虽然已经确定了几种肺腺癌的治疗靶分子，但对肺鳞状细胞癌（LSCC）知之甚少。我们最近报道，CD 271（p75神经营养因子受体）作为肿瘤起始的标志物，是下咽鳞状细胞癌细胞增殖的关键调节因子。在这项研究中，我们发现，CD 271也表达在鳞状细胞癌，但不是在腺癌，几个组织，包括肺，和CD 271的表达与喉鳞状细胞癌预后不良。为了研究CD 271在喉鳞状细胞癌中的作用，我们建立了来自喉鳞状细胞癌患者的异种移植细胞系。在分选的活LSCC细胞群中，CD 271（高）高细胞主要循环通过G（2）/M期，而CD 271（低）细胞大多处于G（0）期。CD 271基因敲低可完全抑制LSCC细胞的增殖和成瘤能力，并增加其细胞周期停滞在G（0）期。在CD 271敲低的细胞中，ERK磷酸化降低，而I κ B α磷酸化、p65磷酸化或Akt磷酸化没有观察到变化。MEK抑制剂U 0126处理可降低LSCC细胞的增殖能力。微阵列分析显示，CD 271敲低减弱了RAS相关通路。TrkB与CD 271形成异源二聚体并加速其下游信号传导，其敲低部分抑制LSCC细胞增殖。这些结果表明，喉鳞状细胞癌的细胞增殖完全依赖于CD 271，部分通过ERK信号激活，CD 271是一个有前途的靶点喉鳞状细胞癌的治疗。
Squamous cell carcinoma is a major type of cancer in the lung. While several therapeutic target molecules for lung adenocarcinoma have been identified, little is known about lung squamous cell carcinoma (LSCC). We recently reported that CD271 (p75 neurotrophin receptor) serves as a marker for tumor initiation and is a key regulator of cell proliferation in hypopharyngeal squamous cell carcinoma. In this study, we found that CD271 was also expressed in squamous cell carcinoma, but not in adenocarcinoma, of several tissues, including the lung, and the expression of CD271 was associated with a poor prognosis in LSCC. To examine CD271's role in LSCC, we established xenograft cell lines from LSCC patients. Within the sorted live LSCC cell population, the CD271(high) high cells were primarily cycling through the G(2)/M phase, while the CD271(low) cells were mostly in the G(0) phase. CD271 knockdown in the LSCC cells completely suppressed their proliferation and tumor-formation capability, and increased their cell-cycle arrest in the G(0) phase. In the CD271-knockdown cells, ERK-phosphorylation was decreased, while no change was observed in the I kappa B alpha-phosphorylation, p65-phosphorylation, or Akt-phosphorylation. Treatment with the MEK inhibitor U0126 decreased the LSCC cells' proliferation capability. Microarray analysis revealed that CD271 knockdown attenuated the RAS-related pathways. The knockdown of TrkB, which forms a heterodimer with CD271 and accelerates its downstream signaling, partially inhibited the LSCC cell proliferation. These results indicated that LSCC exclusively depends on CD271 for cell proliferation, in part through ERK-signaling activation, and CD271 is a promising target for LSCC therapy.