The relative balance between cell growth and cell death is altered in cancers, with the balance tipped towards uncontrolled proliferative capacity in cancer cells [1, 43]. In addition, some cancer cells acquire a markedly enhanced capacity to move, thereby predisposing them to invasion and dissemination [44, 45]. Findings from the present study showed that tumors exhibiting higher levels of expression in MCM2, a marker of proliferation, and gelsolin, a marker of motility, conferred a higher risk of death in NSCLC.
MCM proteins are essential replication initiation factors that ensure the accurate replication of DNA in the cell cycle. Through accurate binding to chromatin during G1 phase and detaching from chromatin during S phase, MCM proteins restrict DNA synthesis to only once per cell cycle [3, 4, 6]. Only licensed origins containing MCM proteins can initiate a pair of replication forks, and once initiation occurs at an origin, the bound MCM proteins are displaced so that the origin cannot fire again . MCM proteins may also function as the helicase that unwinds DNA ahead of each replication fork . Evidence from different organisms and cells indicates that both permanently arrested cells and those in G0 phase have lost expression of MCM proteins and are functionally unlicensed [48–50]. The replication initiation function of MCM proteins in cell cycle implies that they may be valuable markers for proliferation and prognosis in human cancers. Todorov et al. studied MCM2 expression in normal and tumor human tissues and found MCM2 was expressed significantly different in specimens examined, with expression of 97% in tumors but only 27% in normal tissues. Furthermore, the expression level in normal tissues was lower than in tumor tissues, indicating that MCM2 reflects cell proliferation . Dudderidge et al. studied MCM2, geminin, and Ki-67 in renal cell carcinoma and found that MCM2 expression increased dramatically with increasing grade . Hashimoto et al. investigated MCM2 and Ki-67 expression in lung adenocarcinomas and found that the co-expression of MCM2 and Ki-67 at higher levels were significantly associated with poorer survival . The prognostic value of MCM2 was also reported in bladder cancer and oligodendroglioma [40, 51].
Ki-67 is expressed in all stages of the cell cycle except G0 phase, making it a valuable measurement for cell proliferation . In a number of cancers, elevated Ki-67 expression has been found associated with higher aggressiveness and invasiveness [52–54]. The prognostic value of Ki-67 has been observed in cancers of breast, prostate, cervix, and soft tissue . In a comprehensive review, Pugsley et al. noted that higher Ki-67 index was significantly associated with poorer survival in NSCLC in the majority of univariate analyses and in approximately half of the multivariate analyses . In our study, we did not observe the prognostic effect of Ki-67 expression in both the univariate and multivariate analysis, which may be partially due to the limited sample size. The small sample size also prevented additional examination of the prognostic value of MCM2, Ki-67 and gelsolin in subgroup patients. As Pugsley et al. pointed out, factors such as patient heterogeneity, retrospective nature of study design, quantification of immunohistochemistry, and cutoff value may contribute to the inconsistent findings for the prognostic value of Ki-67 NSCLC in the literature .
In addition to proliferation, elevated motility is essential for tumor cells to invade and disseminate [44, 45, 55, 56]. Highly metastatic cells typically exhibit enhanced locomotion capacity compared to less metastatic cells [44, 45, 57, 58]. Various studies have consistently shown that higher levels of motility are associated with higher rates of tumor metastasis or shorter survival time [31–33, 59–62]. The motility facilitating function of gelsolin has been widely observed in animal models [26–29]. We and others have showed that higher levels of gelsolin are associated with poorer survival in breast and lung cancer [31–33]. Some studies failed to find a prognostic significance for gelsolin. However, these studies are generally subject to small sample size or inadequate follow-up time [37, 63–65]. As a generalization, the gelsolin content of the cells in most cancers is found to be down-regulated [37, 64–66], but in a number of studies, researchers found that high gelsolin expression is inversely associated with survival time [31–33]. For example, we found that tumors with high and heterogeneous expression of gelsolin conferred the highest risk of death from NSCLC in patients with this disease . Shieh et al. found that the most potent predictor of poor prognosis was high focal gelsolin expression . Increased expression of gelsolin may facilitate a subset of tumor cells with increased motility, thereby enhancing its capability and probability of invading adjacent tissues and metastasis to remote organ sites [32, 33].