Overexpression of mitogen-activated protein kinase kinase 4 and nuclear factor-κB in laryngeal squamous cell carcinoma: A potential indicator for poor prognosis

Abstract

Abstract. This study aimed to investigate the expression and clinical significance of mitogen-activated protein kinase kinase 4 MKK4 and nuclear factor-κB (NF-κB) in patients with laryngeal squamous cell carcinoma (LSCC). We used immunohistochemistry (IHC) to examine the expression of MKK4 and NF-κB in 78 LSCCs and their adjacent normal tissues. To clarify the validity of MKK4 and NF-κB as determined by the IHC analysis, RT-PCR was performed on 21 tissues randomly selected from the 78 LSCCs. The positive expression rates of MKK4 and NF-κB in patients with LSCC were 67.9% (53/78) and 60.3% (47/78) respectively, which were significantly higher than those in the adjacent normal tissue (both P<0.01). The positive expression of MKK4 and NF-κB tended to be associated positively with lymph node metastasis (both P<0.01) as well as T stage (both P<0.01). The Spearman analysis indicated that the expression level of MKK4 was positively correlated with that of NF-κB significantly (rs=0.368, P<0.01). Overall survival curves estimated by Kaplan-Meier showed that tumor patients with low MKK4 and NF-κB expression in their tumor cells survive significantly longer than patients with high MKK4 and NF-κB levels (P=0.027, and P<0.01, respectively). In addition, multivariate Cox regression analysis showed that N stage, T stage and NF-κB expression are significant independent prognostic factors for overall survival (P<0.01, P=0.014, and P=0.027, respectively). These findings suggested that the expression of MKK4 and NF-κB may be considered as a useful prognostic marker of LSCC after surgical resection.

Nutlin-3 overcomes arsenic trioxide resistance and tumor metastasis mediated by mutant p53 in Hepatocellular Carcinoma

“…However, the intracellular arsenical of HepG2/As was increased and reached 0.066 μg/10 6 cells, when arsenic trioxide was applied with 20 μM Nutlin-3 for 2 h. The intracellular arsenical of SMMC7721/As was strongly accumulated and reached 0.224 μg/10 6 cells after the treatment of both arsenic trioxide and Nutlin-3. It’s worth to note that 40 μM verapamil (a p-gp inhibitor) induced accumulation of arsenical in HepG2/As and SMMC7721/As (0.083 and 0.24 μg/10 6 cells respective) as same as 20 μM Nutlin-3, which was coincident with our previous results [5]. …”

“…Nutlin-3 could also induce apoptosis in the parental HCC cells, but not in the resistant cells (Figure  1C). As in our previous study [5], the expression of MDM2, p-gp, and p53 were all increased in arsenic resistant cells compared with that in the parental cells (Figure  1D).…”

“…However, a recent phase II trial showed that single agent arsenic trioxide was poorly effective against advanced liver cancer with failure to increase the five-year survival rates [4], which was inconsistent with the in vitro reports. Although lots of factors could explain the inefficacy of arsenic trioxide in liver cancer patients, anti-cancer drug resistance might be the most important reason for this problem [5]. …”

“…It was reported that the As-GSH conjugates is substrates of some ABC transporter proteins and could be pumped out by the ABC superfamily members [6,7]. In our previous study, we found that arsenic trioxide resistant HCC cells overexpressed p-glycoprotein (p-gp), which could decrease the intra-cellular arsenicals [5]. The resistant cells also overexpressed MDM2, which could inactivate p53 or p73, leading to the defence of apoptosis induced by arsenic trioxide.…”

Modulating autophagy: a strategy for cancer therapy

“…These findings suggest that the As 2 O 3 -induced effects depend on the tumor tissue type: it triggers autophagy in solid tumors, whereas it induces cell death by apoptosis in hematological neoplasms. Currently, As 2 O 3 is in clinical trials in gliomas, advanced solid tumors, metastatic liver cancer, and pediatric solid tumors[99],[100].…”