Dobashi Y, Watanabe H, Sato Y, Hirashima S, Yanagawa T, Matsubara H, Ooi A
Department of Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
J Pathol. 2006 Dec;210(4):431-40. doi: 10.1002/path.2069.
To clarify the involvement of autocrine motility factor (AMF) in the phenotype and biological profiles of human lung carcinomas, we analysed protein and mRNA expression in a total of 180 cases. Immunohistochemistry revealed positive staining in 67.2%, with the highest frequency in squamous cell carcinoma (SCC; 90.8%) and the lowest in small cell carcinoma (SmCC; 27.8%). In SCC, the staining frequency and intensity correlated with the degree of morphological differentiation. Generally, the expression levels in immunoblotting analysis corresponded well with immunohistochemical positivity. However, there was less agreement between protein and mRNA levels: in SmCC and large cell carcinomas (LCCs), mRNA showed higher, but protein showed lower expression. Among non-small cell lung carcinomas (NSCLCs), AMF protein levels correlated inversely with tumour size, but tumours exhibiting lymph node metastasis showed higher mRNA expression. In cultured lung carcinoma cells which comprised all histological subtypes, AMF was detected in the lysates of all ten cell lines. Secreted AMF protein was detected in the conditioned media from six cell lines, most of which were SmCC or LCC. Thus, a particular subset of lung carcinomas secrete AMF, which may promote cell motility via autocrine stimulation through its cognate receptor and cause the biological aggressiveness seen in SmCC and LCC. Moreover, treatment by proteasome inhibitors resulted in increased cellular AMF in five cell lines, suggesting that intracellular AMF levels are regulated by both secretion and proteasome-dependent degradation. In conclusion, AMF was detected in a major proportion of lung carcinomas, and may play a part not only in proliferation and/or progression of the tumours, but also, possibly, in the differentiation of SCC. Furthermore, higher mRNA expression may be related to the high metastatic potential of NSCLC and increased protein secretion, leading to a more aggressive phenotype, such as the invasiveness of SmCC and LCC.
为阐明自分泌运动因子（AMF）在人肺癌表型和生物学特征中的作用，我们分析了总共180例病例中的蛋白质和mRNA表达情况。免疫组织化学显示阳性染色率为67.2%，其中鳞状细胞癌（SCC）的阳性率最高（90.8%），小细胞癌（SmCC）的阳性率最低（27.8%）。在SCC中，染色频率和强度与形态学分化程度相关。一般来说，免疫印迹分析中的表达水平与免疫组织化学阳性结果相符。然而，蛋白质和mRNA水平之间的一致性较差：在SmCC和大细胞癌（LCC）中，mRNA表达较高，但蛋白质表达较低。在非小细胞肺癌（NSCLC）中，AMF蛋白水平与肿瘤大小呈负相关，但发生淋巴结转移的肿瘤显示出较高的mRNA表达。在包含所有组织学亚型的培养肺癌细胞中，在所有十个细胞系的裂解物中均检测到AMF。在六个细胞系的条件培养基中检测到分泌的AMF蛋白，其中大多数是SmCC或LCC。因此，肺癌的一个特定亚群分泌AMF，它可能通过其同源受体的自分泌刺激促进细胞运动，并导致SmCC和LCC中所见的生物学侵袭性。此外，蛋白酶体抑制剂处理导致五个细胞系中的细胞AMF增加，表明细胞内AMF水平受分泌和蛋白酶体依赖性降解的调节。总之，在大部分肺癌中检测到AMF，它可能不仅在肿瘤的增殖和/或进展中起作用，而且可能在SCC的分化中起作用。此外，较高的mRNA表达可能与NSCLC的高转移潜能和增加的蛋白质分泌有关，导致更具侵袭性的表型，如SmCC和LCC的侵袭性。
