Brandl Lydia, Horst David, Grünewald Thomas G P, Mayerle Julia, Sendelhofert Andrea, Neumann Jens, Kirchner Thomas, De Toni Enrico N
Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Institute of Pathology, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Cell Physiol Biochem. 2019;53(5):820-831. doi: 10.33594/000000175.
BACKGROUND/AIMS: MLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens.
This study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples.
Loss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors.
By providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.
背景/目的：MLK4（KIAA1804）是微卫星稳定（MSS）结直肠癌（CRC）中第二常见的突变激酶。已知该分子可调节不同的生理细胞过程，包括细胞周期、衰老和凋亡，并且已有机制证据表明MLK4在致癌过程中发挥作用。然而，这种激酶发挥肿瘤抑制作用还是致癌功能仍存在争议。本研究旨在通过调查人类肿瘤标本阐明MLK4在CRC发病机制中的作用。
本研究通过免疫组织化学评估了204例早期CRC患者手术肿瘤样本中MLK4的表达水平及其与各种临床病理特征和患者预后的相关性。此外，在一个由786例结肠癌样本组成的独立队列中分析了MLK4 mRNA转录情况。
在单因素分析中，MLK4染色缺失与CRC患者较差的总生存期（OS）和无进展生存期（PFS）相关（OS：101个月对164个月，p = 0.0002；PFS：85个月对125个月，p = 0.0001），在多因素分析中也是如此（OS：HR = 1.70；p = 0.001；PFS：HR = 1.61；p = 0.001）。这在第二个独立队列中对MLK4 mRNA的分析中得到了证实。根据KRAS突变状态进行的亚组分析表明，在KRAS突变病例（HR分别为2.77；p = 0.0001和HR = 2.31；p = 0.0003）和微卫星稳定肿瘤（HR = 1.87；p = 0.002和HR = 1.06；p = 0.006）中，MLK4染色与更好的OS和PFS相关，但在KRAS野生型和微卫星不稳定肿瘤中并非如此。
通过提供关于MLK4预后意义的首份临床标本报告，我们确定了这种激酶的致癌性功能丧失，并提示其在与KRAS信号相互作用以决定CRC侵袭性表型中可能发挥的作用。这些发现值得在更广泛的队列和各种临床环境中对MLK4进行进一步研究。
