Prognostic significance of mammalian sterile20-like kinase 1 in colorectal cancer

Abstract

Mammalian Sterile20-like kinase 1 (Mst1) is a member of the yeast Ste20-related kinase family known to be involved in the process of apoptosis initiated by a variety of stimuli. The aim of this study was to determine the prognostic significance of Mst1 expression in colorectal cancer. A series of 1197 mismatch-repair-proficient colorectal cancers retrieved from a tissue microarray were randomized into two study groups. On the first group (n ¼ 599) receiver operating characteristic curves were used to determine the most clinically useful cutoffs to describe Mst1 expression with respect to T stage, N stage, tumor grade, vascular invasion and overall survival. The association of Mst1 expression and each outcome was immunohistochemically evaluated on the second study group (n ¼ 598) as well as on a third study group comprising 141 mismatch-repair-deficient colorectal cancers. A univariate analysis in the second study group showed that loss of cytoplasmic Mst1 was associated with higher T stage (P ¼ 0.001), higher N stage (P ¼ 0.029), vascular invasion (P ¼ 0.017) and overall survival (P ¼ 0.014). Nuclear Mst1 expression was not significantly associated with N stage, T stage or vascular invasion but was associated with tumor grade. In mismatch-repair-deficient colorectal cancers, loss of cytoplasmic Mst1 was associated with higher N stage (P ¼ 0.019) and shortened survival (P ¼ 0.0001). In a multivariate analysis, loss of cytoplasmic Mst1 was an independent adverse prognostic factor in this group of patients. Methylation analysis on 32 cases showed that the loss of cytoplasmic Mst1 expression is not likely due to promoter methylation. In summary, loss of cytoplasmic Mst1 expression is a marker of tumor progression in mismatchrepair-proficient as well as mismatch-repair-deficient colorectal cancers. These results are suggestive of a tumor suppressor role for Mst1 in human colorectal cancer.

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Similar to YAP overexpression, ablation of the Hippo pathway components Mer and Sav and double knockout of Mst1/2 in mice result in liver enlargement and tumor formation characteristic of HCC and cholangiocarcinoma (CC) (Zhou et al, 2009;Benhamouche et al, 2010;Lee et al, 2010;Lu et al, 2010;Song et al, 2010;. Aberrant Mst1/2 and Lats1/2 expression is observed in human cancers (Hisaoka et al, 2002;Jimé-nez-Velasco et al, 2005;Takahashi et al, 2005;Jiang et al, 2006;Minoo et al, 2007;Seidel et al, 2007;Cho et al, 2009;Zhou et al, 2009). Lats2 is also found mutated in human mesothelioma cell lines and non-small cell lung cancer (Strazisar et al, 2009;Murakami et al, 2011).…”

Snapshots of a hybrid transcription factor in the Hippo pathway

“…Mutations of the pathway components, such as NF2, WW45 and MOB1, have been linked to several types of human cancers (Tapon et al, 2002;Lai et al, 2005;Asthagiri et al, 2009). Downregulation of MST1/2, LATS1/2 and MOB1 has been observed in human sarcomas and various cancers (Hisaoka et al, 2002;Jiménez-Velasco et al, 2005;Takahashi et al, 2005;Kosaka et al, 2007;Minoo et al, 2007;Seidel et al, 2007). The main output of the Hippo pathway is to suppress the function of YAP by regulating its nuclear translocation and stability.…”

Increased oncogenic microRNA-18a expression in the peripheral blood of patients with prostate cancer: A potential novel non-invasive biomarker

“…By contrast, miR-18a knockdown in nude mice was demonstrated to decrease prostate tumor growth and induce apoptosis (16). STK4 is a proapoptotic protein that was identified as a tumor suppressor in cancer cells (31,32). Therefore, inhibition of The results of the current study demonstrated that the expression of peripheral blood miR-18a was significantly higher in patients with PC than in BPH patients and healthy control individuals.…”