Myeloid cell leukemia-1 is an important predictor of survival and progression of small cell lung cancer

Abstract

Background: Small cell lung cancer (SCLC) is the most fatal malignancy for which more effective therapies are urgently needed. Overexpression of myeloid cell leukemia-1 (Mcl-1) has been demonstrated to be one of the most common genetic alterations among different types of tumor/cancer, which induces resistance against various anti-cancer therapies including cisplatin. The study aimed to explore the role of Mcl-1 in the prognosis and resistance to anti-cancer therapy in patients with SCLC.

Methods: Patients with SCLC were recruited from those enrolled/treated in Sun Yat-sen University Cancer Center. Their specimens were collected for immunohistochemical evaluation. We compared the baseline characteristics, response to chemotherapy and overall survival (OS) of the patients with different expression levels of Mcl-1.

Results: The expression level of Mcl-1 was significantly lower in patients with limited stage SCLC than in those with extensive stage SCLC (P=0.014). Based on the median value of Mcl-1 expression level, the patients were divided into high and low Mcl-1 groups, respectively. Univariate analysis revealed that low Mcl-1 expression was associated with a significant improvement in OS, with a hazard ratio (HR) of 0.538. Multivariate analysis confirmed the independent prognostic value of Mcl-1 expression level (P=0.014). Moreover, we found a significantly close relationship between higher Mcl-1 expression level and shorter time to progression (TTP) of the patients received chemotherapy (P=0.040).

Conclusions: Our findings demonstrated that Mcl-1 expression level was a prognostic biomarker for survival outcomes and cancer progression in the patients with SCLC. Thus, it could be used as a valuable biomarker in identifying those patients with high risk of treatment failure.

Keywords: Myeloid cell leukemia-1 (Mcl-1); overall survival (OS); prognosis; small cell lung cancer (SCLC); time to progression (TTP).

Figure 1

Flow chart of patients’ enrollment. SCLC, small cell lung cancer.

Figure 2

Representative images of immunostaining of Mcl-1 expression with different scores. (A) High expression level of Mcl-1 (magnification, ×20); (B) high expression level of Mcl-1 (magnification, ×40); (C) low expression level of Mcl-1 (magnification, ×20); (D) low expression level of Mcl-1 (magnification, ×40); (E) the negative expression level of Mcl-1 (magnification, ×20); (F) the high expression level of Mcl-1 (magnification, ×40). The tissue sections were dewaxed in xylene, rehydrated, and rinsed in graded ethanol solutions. The antigens were retrieved by heating the tissue sections at 100 °C for 5 min in EDTA (1 mmol/L, pH 9.0) solution when necessary, and then immersed in a 0.3% hydrogen peroxide solution for 10 min to block endogenous peroxidase activity, rinsed in phosphate buffered saline (PBS) for 5 min, and incubated with the MCL-1 primary antibody (1:100 dilution, CST#39224; Cell Signaling Technology) at 4 °C overnight. The slides were washed with 1× PBS and treated with a goat antibody against a rabbit secondary antibody (EnVision; Dako, Glostrup, Denmark) at 37.5 °C for 30 min. Finally, the visualized staining was developed with 3,3’-diaminobenzidine tetrahydrochloride (DAB, Dako, Glostrup, Denmark), and all of the slides were counterstained with hematoxylin. Mcl-1, myeloid cell leukemia-1.

Figure 3

Kaplan-Meier survival curves comparing TTP: low Mcl-1 expression level vs. high Mcl-1 expression level. Mcl-1, myeloid cell leukemia-1; TTP, time to progression.

Figure 4

Kaplan-Meier survival curves comparing OS. (A) Low Mcl-1 expression vs. high Mcl-1 expression; (B) limited stage vs. extensive stage. OS, overall survival; Mcl-1, myeloid cell leukemia-1.