Research Institute of Molecular Pathology, Dr. Bohr-Gasse 3, A-1030, Vienna, Austria.
Department of Medicine I, Division of Oncology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090, Vienna, Austria.
J Exp Clin Cancer Res. 2021 Feb 17;40(1):69. doi: 10.1186/s13046-021-01862-5.
Gene amplification of MET, which encodes for the receptor tyrosine kinase c-MET, occurs in a variety of human cancers. High c-MET levels often correlate with poor cancer prognosis. Interleukin-like EMT inducer (ILEI) is also overexpressed in many cancers and is associated with metastasis and poor survival. The gene for ILEI, FAM3C, is located close to MET on chromosome 7q31 in an amplification "hotspot", but it is unclear whether FAMC3 amplification contributes to elevated ILEI expression in cancer. In this study we have investigated FAMC3 copy number gain in different cancers and its potential connection to MET amplifications.
FAMC3 and MET copy numbers were investigated in various cancer samples and 200 cancer cell lines. Copy numbers of the two genes were correlated with mRNA levels, with relapse-free survival in lung cancer patient samples as well as with clinicopathological parameters in primary samples from 49 advanced stage colorectal cancer patients. ILEI knock-down and c-MET inhibition effects on proliferation and invasiveness of five cancer cell lines and growth of xenograft tumors in mice were then investigated.
FAMC3 was amplified in strict association with MET amplification in several human cancers and cancer cell lines. Increased FAM3C and MET copy numbers were tightly linked and correlated with increased gene expression and poor survival in human lung cancer and with extramural invasion in colorectal carcinoma. Stable ILEI shRNA knock-down did not influence proliferation or sensitivity towards c-MET-inhibitor induced proliferation arrest in cancer cells, but impaired both c-MET-independent and -dependent cancer cell invasion. c-MET inhibition reduced ILEI secretion, and shRNA mediated ILEI knock-down prevented c-MET-signaling induced elevated expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Combination of ILEI knock-down and c-MET-inhibition significantly reduced the invasive outgrowth of NCI-H441 and NCI-H1993 lung tumor xenografts by inhibiting proliferation, MMP expression and E-cadherin membrane localization.
These novel findings suggest MET amplifications are often in reality MET-FAM3C co-amplifications with tight functional cooperation. Therefore, the clinical relevance of this frequent cancer amplification hotspot, so far dedicated purely to c-MET function, should be re-evaluated to include ILEI as a target in the therapy of c-MET-amplified human carcinomas.
MET 基因扩增，其编码受体酪氨酸激酶 c-MET，发生在多种人类癌症中。高 c-MET 水平常与癌症预后不良相关。白细胞介素样 EMT 诱导物 (ILEI) 在许多癌症中也过表达，并与转移和不良预后相关。ILEI 的基因 FAM3C 位于染色体 7q31 上的 MET 附近的扩增“热点”中，但尚不清楚 FAMC3 扩增是否导致癌症中 ILEI 表达升高。在这项研究中，我们研究了不同癌症中 FAMC3 拷贝数增益及其与 MET 扩增的潜在联系。
在各种癌症样本和 200 个癌细胞系中研究 FAMC3 和 MET 拷贝数。这两个基因的拷贝数与 mRNA 水平相关联，并与肺癌患者样本中的无复发生存率以及 49 例晚期结直肠癌患者原发样本中的临床病理参数相关联。然后研究了 ILEI 敲低和 c-MET 抑制对五种癌细胞系的增殖和侵袭性以及在小鼠中的异种移植肿瘤生长的影响。
FAMC3 与几种人类癌症和癌细胞系中的 MET 扩增密切相关。增加的 FAM3C 和 MET 拷贝数紧密相关，并与人类肺癌中的基因表达增加和预后不良以及结直肠癌中的外膜浸润相关联。稳定的 ILEI shRNA 敲低不影响增殖或对癌细胞中 c-MET 抑制剂诱导的增殖抑制的敏感性，但会损害 c-MET 独立和依赖的癌细胞侵袭。c-MET 抑制减少了 ILEI 的分泌，而 shRNA 介导的 ILEI 敲低可防止 c-MET 信号诱导的基质金属蛋白酶 (MMP)-2 和 MMP-9 的表达和分泌升高。ILEI 敲低和 c-MET 抑制的联合使用可通过抑制增殖、MMP 表达和 E-钙粘蛋白膜定位显著减少 NCI-H441 和 NCI-H1993 肺肿瘤异种移植物的侵袭性生长。
这些新发现表明，MET 扩增通常实际上是 MET-FAM3C 共扩增，具有紧密的功能合作。因此，这个频繁的癌症扩增热点的临床相关性，迄今为止专门用于 c-MET 功能，应该重新评估，将 ILEI 作为治疗 c-MET 扩增的人类癌的靶点。
