Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer.
Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer.
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DOI：
10.1093/jnci/djy166
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发表时间：
2018-11
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影响因子：
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通讯作者：
Rongqiang Yang;Steven W. Li;Zirong Chen;Xin Zhou;W. Ni;Dongtao A. Fu;Jianrong Lu;F. Kaye;Lizi Wu
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作者：
Rongqiang Yang;Steven W. Li;Zirong Chen;Xin Zhou;W. Ni;Dongtao A. Fu;Jianrong Lu;F. Kaye;Lizi Wu
背景LKB 1抑癌基因在非小细胞肺癌（NSCLC）中通常是失活的，NSCLC是肺癌的一种主要形式。目前还没有针对LKB 1失活肺癌的靶向治疗。鉴定LKB 1失活下游的关键信号组分有可能发现合理的治疗靶点。在这里，我们研究了胰岛素/IGF/松弛素超家族成员INSL 4在LKB 1失活的NSCLC中的作用。方法采用转录组全谱分析、定量逆转录PCR、Western印迹、酶联免疫吸附试验和RNA原位杂交等方法，分析INSL 4在人NSCLC细胞系和肿瘤标本中的表达。使用对数秩和Fisher精确检验分析来自癌症基因组图谱肺腺癌（n = 515）的INSL 4基因表达和临床数据。使用短发夹RNA（shRNA）敲低、过表达、转录组分析、细胞生长和存活测定在体外和体内研究了INSL 4功能。所有统计检验均为双侧检验。结果INSL 4是LKB 1缺陷的新下游靶点，其表达是通过CRTC-CREB异常激活诱导的。INSL 4在LKB 1缺陷型NSCLC细胞（高达543倍）和41例原发性肿瘤中的9例中高度诱导，尽管在除胎盘外的所有正常组织中均检测不到。来自癌症基因组图谱的具有高和低INSL 4表达的肺腺癌（以前10百分位数作为截止值）在晚期肿瘤分期（P <0.001）、淋巴结转移（P = 0.001）和肿瘤大小（P = 0.01）方面显示出统计学显著差异。INSL 4-高组显示出比INSL 4-低组更差的存活率（P < .001）。在体外和小鼠异种移植模型（每组n = 5只小鼠）中，LKB 1灭活的NSCLC细胞的生长和活力需要持续的INSL 4表达。表达谱显示INSL 4是细胞周期、生长和存活的关键调节因子。结论LKB 1缺陷诱导自分泌INSL 4信号通路，对肺癌细胞的生长和存活起关键作用。因此，异常的INSL 4信号传导是LKB 1缺陷型肺癌的有希望的治疗靶点。
Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.