[Cdc37 Expression in Multiple Myeloma and Its Role in Cell Proliferation].

OBJECTIVE: To investigate the expression of cell division cycle protein 37 (Cdc37) in multiple myeloma (MM) and its effect on MM cell proliferation. METHODS: The expression of Cdc37 mRNA in CD138+ cells derived from 63 newly diagnosed MM patients and 8 healthy people were detected by real-time quantitative PCR (RT-qPCR). Cdc37 was down-regulated by lentivirus in MM cell line NCI-H929. CCK-8 assay and soft agar clone formation assay were conducted to explore the role of Cdc37 on MM proliferation in vitro. To further verify the effect of Cdc37 on MM cell proliferation in vivo, NOD/SCID mice subcutaneous tumorigenesis model was established. Flow cytometry was carried out to explore the role of Cdc37 on cell cycle. Cell cycle associated proteins and NF-κB pathway were detected by Western blot (WB). RESULTS: Cdc37 was highly expressed in newly diagnosed CD138+cells compared with healthy people. After Cdc37 suppression by shRNA lentivirus infection in NCI-H929 cells, the proliferation of MM cells were decreased in vitro and in vivo. Compared with the control group, the ratio of cells arrested in G0/G1 phase significantly increased in NCI-H929-Cdc37 shRNA cells, the expression of cyclin D1 decreased, while the expression of p21 and p53 was significantly up-regulated. Meanwhile, the activation of NF-κB signaling pathway was hampered in NCI-H929-Cdc37 shRNA cells. CONCLUSION: Cdc37 is highly expressed in newly diagnosed MM patients. Inhibition of Cdc37 results in decreased proliferation activity and G0/G1 arrest in NCI-H929 cells. The possible mechanism may be to inhibit the activation of NF-κB signaling pathway.

Secretory status of monoclonal immunoglobulin is related to the outcome of patients with myeloma: a retrospective study.

The treatment of multiple myeloma (MM) with proteasome inhibitor (PI) bortezomib has significantly improved the survival of patients with MM. The 26S proteasome inhibitor targets the unfolded protein response (UPR) by inhibiting proteasome degradation of ubiquitinated paraprotein, subsequently leading to the lethal accumulation of paraprotein within the endoplasmic reticulum. According to secretory status of monoclonal immunoglobulin, newly diagnosed MM (NDMM) is divided into measurable and unmeasurable disease, which includes oligosecretory, nonsecretory, and nonproducer myeloma. The present study analyzed the clinical characteristics of 822 patients with NDMM who had either measurable or unmeasurable diseases and received bortezomib- or thalidomide-based therapies. Our results showed that the median progression-free survival (PFS) and overall survival (OS) of patients with MM was significantly longer in patients with measurable disease than those in oligosecretory, nonsecretory, and nonproducer MM (PFS: 27, 18, 19, and 2.0 months, respectively [P < .001]; OS: 51, 30, 22, and 2.0 months, respectively [P < .001]). Within the unmeasurable group, patients with nonproducer myeloma showed the shortest PFS and OS. Importantly, compared with thalidomide treatment, bortezomib significantly improved the PFS and OS of patients with MM with measurable disease (PFS: 25 and 33 months [P = .022], respectively; OS: 41 and 58 months [P < .001], respectively), but not those with unmeasurable disease (PFS: 18 and 16 months [P = .617], respectively; OS: 22 and 27 months [P = .743], respectively). Our results indicate that bortezomib-based therapy performed no better than thalidomide-based treatment in patients with unmeasurable MM. The results need to be confirmed in other patient cohorts, preferably in the context of a prospective trial.

[Expression of SOX11 mRNA in mantle cell lymphoma and its clinical significance].

OBJECTIVE: To investigate the expression level of SOX11 mRNA in mantle cell lymphoma (MCL) and other B-cell non-Hodgkin lymphoma (B-NHL) and its prognostic value in MCL. METHODS: The expression level of SOX11 mRNA in 80 B-NHL patients were determined by real-time quantitative RT-PCR, GAPDH was used as internal control. The dispersion of SOX11 expression ratio of groups with different prognostic factors was described by Mann-Whitney U test. RESULTS: The SOX11 mRNA expression level was 2.90 (0.75 - 4.63) in 80 B-NHL patients, and the expression level was significantly higher in MCL than that in other B-NHL (P = 0.014). The SOX11 expression level was statistically lower in the group of MCL with hyperleukocytosis, 12 trisomy, MYC amplification and therapeutic effect < PR (P = 0.042, 0.013, 0.028, 0.009) than that of MCL in other group. But SOX11 expression was not associated with MCL international prognostic index (MIPI) (P = 0.333), lactate dehydrogenase (LDH) (P = 0.790), ATM mutation (P = 0.865) and P53 deletion (P = 0.116). The progression free survival (PFS) and overall survival (OS) were significantly longer in the MCL patients with high level of SOX11 than that of other MCL patients. CONCLUSION: There was statistically significant differences in SOX11 mRNA expression between MCL with other B-NHL. SOX11 maybe a good prognostic factor in MCL.

[Regulation of miRNA-15a/-16 expression on the drug resistance of myeloma cells].

OBJECTIVE: To explore the effects and mechanism of bone marrow stromal cells (BMSCs) on the drug resistance of multiple myeloma (MM). METHODS: Fresh untreated MM patient (5 samples) and health donor (5 samples) bone marrow samples were collected from May 2011 to July 2011 at our hospital. Their BMSCs were separated respectively. The supernatant expression of cytokines in BMSCs was detected by enzyme-linked immunosorbent assay (ELISA). Myeloma cells were co-cultured with BMSCs and treated with melphalan or bortezomib. Cell proliferation and miRNA-15a/-16 expression of myeloma cells were measured in different culture conditions with thiazoyl blue tetrazolium bromide (MTT) assay and quantitative real-time PCR (qRT-PCR). miRNA-15a was transfected into myeloma cells. And the miRNA-15a functions on cell cycle and cell apoptosis were detected by flow cytometry. RESULTS: ELISA assay showed that cytokine IL-6 and VEGF were at higher levels in MM-BMSCs than healthy BMSCs ((189 ± 9) vs (115 ± 15) pg/ml, (1497 ± 40) vs (1239 ± 21) pg/ml, both P < 0.05). The miRNA-15a/-16 expressions of myeloma cells were up-regulated after the treatment of melphalan and bortezomib (all P < 0.05). However, the miRNA-15a/-16 up-regulation by melphalan or bortezomib became inhibited when MM cells were co-cultured with MM-BMSCs (melphalan: 4.690 ± 0.050 vs 34.440 ± 4.100, 0.760 ± 0.070 vs 12.030 ± 1.020, bortezomib: 1.440 ± 0.230 vs 11.480 ± 1.488, 0.880 ± 0.040 vs 3.680 ± 0.420, all P < 0.05). Furthermore, IL-6 suppressed the expression of miRNA-15a/-16 in a dose and time-dependent pattern. The transfection of miRNA-15a led to the arrest of MM cell cycle in G(1)/S phase. CONCLUSIONS: BMSCs suppress the proliferation of myeloma cells and regulate the drug sensitivity of myeloma cells through the inhibited expression of miRNA-15a/-16. IL-6 plays a pivotal role in the occurrence of drug resistance.