Depression induces poor prognosis associates with the down-regulation brain derived neurotrophic factor of serum in advanced small cell lung cancer

Abstract

Patients with lung cancer often experience a state of depression, and these conditions may severely affect their quality of life (QoL) and prescription compliance. The current study was conducted to delineate the complex links between depression and the prognosis of patients with small cell lung cancer (SCLC) and the underlying mechanism was also explored.186 patients who received platinum-based chemotherapy for newly diagnosed stage III or stage IV SCLC were enrolled. The Self-Rating Depression Scale (SDS) questionnaire was completed the day before the start of chemotherapy to assess the depression status of the patients. Patients with stage IV SCLC or lower BMI have higher depression scores. In terms of the adverse effects of chemotherapy, depression severely decreases patient tolerance to chemotherapy and their QoL score (R2 = 0.2385) and is also associated with severe vomiting (P < 0.001), leukopenia (R2 = 0.2332), and prolonged hospital stay (R2 = 0.1961). More importantly, severe depression reduces the PFS (R2 = 0.1943) and OS (P < 0.01) of the patients. We found that patients with severe depression displayed a downregulated level of serum BDNF and that the level of serum BDNF was highly correlated with the OS of the patients (R2 = 0.2292). Using the MTT cell viability assay in vitro, we observed that cotreatment with BDNF clearly enhanced the chemosensitivity of NCI-H69 tumor cells to Cisplatin and induced the downregulation of ABCG2.Based on this evidence, it appears that a relationship does exist between depression and prognosis in SCLC and that the mechanism by which depression affects prognosis is achieved via the downregulation of BDNF expression.

Keywords: ABCG2; brain derived neurotrophic factor; chemotherapy; depression; small cell lung cancer.

Figure 1. Depression status increased the adverse effects of chemotherapy and decreased the quality of life

(A) SDS score increased significantly with a rise in the level of CINV. (B) an inverse correlation between depression and leukopenia was observed, which indicates that depression significantly reduced the incidence of leukopenia in patients with SCLC. (C) depression significantly prolonged the hospitalization stay of patients. (D) depression significantly reduced the quality of life of patients.

Figure 2. Depression reduced progression-free survival time and overall survival outcomes

(A) A correlation analysis revealed a significant negative correlation between depression and progression-free survival. (B) patients were divided into three group according to SDS scores, and patients in the mild depression group had a longer survival time than patients in the severe and moderate depression groups (P < 0.01).

Figure 3. Depression mediated the BDNF level in patients

(A) Patients with mild depression had a significantly higher level of serum BDNF than those with moderate and severe depression. However, the level of serum BDNF between the moderate depression group was not significantly different from that of the severe depression group. (B) BDNF demonstrated a significant positive correlation with OS, and a higher serum BDNF level prolonged the OS of patients.

Figure 4. BDNF increased the chemosensitivity of NCI-H69 cells

(A) Water-soluble BDNF at 3 concentrations (1 mg/ml, 5 mg/ml, 25 mg/ml) had no significant effect on cell proliferation. NCI-H69 cells were cultured in medium with different concentrations of BDNF (1 mg/ml, 5 mg/ml or 25 mg/ml) and were incubated for 24 hours; they were then tested for chemosensitivity to Cisplatin by MTT assay. (B) Chemosensitivity was significantly increased in the BDNF group after exposure to Cisplatin and demonstrated a dose-effect relationship. (C) The IC₅₀ of NCI-H69 cells cultured with BDNF was clearly decreased compared with that in control cells. (^**P < 0.01, ^***P < 0.001).

Figure 5. ABCG2 was downregulated by BDNF and depression

(A) The mRNA expression of ABCG2 was downregulated in NCI-H69 cells co-cultured with BDNF (25 mg/ml); then, NCI-H69 cells were exposed to different concentrations of BDNF in culture (1 mg/ml, 5 mg/ml or 25 mg/ml). (B) Western blot analysis revealed that cells in the BDNF culture group showed a marked decrease in ABCG2 expression. (C) The relative ABCG2 expression in cells cultured with BDNF was quantified by Western blot and was found to be significantly higher than that in the controls. (D) Immunohistochemical analysis revealed that the tumors of patients in the severe depression group demonstrated strong expression of ABCG2. (E) The % positive area for ABCG2 staining in tumors from patients with severe depression was 15.6-fold higher than in patients with mild depression.