Chemotherapy-initiated cysteine-rich protein 61 decreases acute B-lymphoblastic leukemia chemosensitivity.

PURPOSE: Chemoresistance is a major challenge for acute lymphoblastic leukemia (ALL) treatment. Cysteine-rich protein 61 (Cyr61) plays an important role in drug resistance modulation of tumor cells, and Cyr61 levels are increased in the bone marrow of patients with ALL and contribute to ALL cell survival. However, the effect of Cyr61 on B cell acute lymphoblastic leukemia (B-ALL) cell chemosensitivity and the regulatory mechanisms underlying Cyr61 production in bone marrow remain unknown. METHODS: Nalm-6 and Reh human B-ALL cell lines were used in this study. Cyr61 levels were assessed using quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The effect of Cyr61 on B-ALL cell chemosensitivity to daunorubicin (DNR) was evaluated using cell viability and flow cytometry analyses. The regulatory mechanisms of Cyr61 production in bone marrow were examined using qRT-PCR and western blot analysis. RESULTS: Cyr61 knockdown and overexpression increased and decreased the chemosensitivity of B-ALL cells to DNR, respectively. Cyr61 attenuated chemotherapeutic drug-induced apoptosis by upregulating B cell lymphoma-2. Notably, DNR induced DNA damage response and increased Cyr61 secretion in B-ALL cells through the ataxia telangiectasia mutated (ATM)-dependent nuclear factor kappa B pathway. CONCLUSION: DNR induces Cyr61 production in B-ALL cells, and increased Cyr61 levels reduce the chemosensitivity of B-ALL cells. Consequently, targeting Cyr61 or related ATM signaling pathway may present a promising treatment strategy to enhance the chemosensitivity of patients with B-ALL.

S100A6 mediated epithelial-mesenchymal transition affects chemosensitivity of colorectal cancer to oxaliplatin.

PURPOSE: To investigate the mechanism by which S100 calcium-binding protein A6 (S100A6) affects colorectal cancer (CRC) cells to oxaliplatin (L-OHP) chemotherapy, and to explore new strategies for CRC treatment. METHODS: S100A6 expression was assessed in both parental and L-OHP-resistant CRC cells using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assays (ELISA). Lentiviral vectors were utilized to induce the knockdown of S100A6 expression, followed by comprehensive evaluations of cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT). Additionally, RNA-seq analysis was conducted to identify genes associated with the knockdown of S100A6. RESULTS: Elevated S100A6 expression in CRC tissues correlated with an adverse prognosis in patients with CRC. Higher expression of S100A6 was also observed in L-OHP-resistant CRC cells, which showed enhanced proliferation, migration, invasion, and antiapoptotic capabilities. Notably, the knockdown of S100A6 expression resulted in decreased proliferation, increased apoptosis, and suppression of EMT and tumorigenicity in L-OHP-resistant CRC cells. Transcriptome sequencing reveals a noteworthy association between S100A6 and vimentin expression. Application of the EMT agonist, transforming growth factor ß (TGF-ß), induces EMT in CRC cells. S100A6 expression positively correlates with TGF-ß expression. TGF-ß facilitated the expression of EMT-related molecules and reduced the chemosensitivity of L-OHP in S100A6-knockdown cells. CONCLUSION: In conclusion, the knockdown of S100A6 may overcome the L-OHP resistance of CRC cells by modulating EMT.

[Effect of Cyr61 on Imatinib Resistance in Chronic Myeloid Leukemia and Its Mechanism].

OBJECTIVE: To investigate the effect of Cyr61 on imatinib (IM) resistance in chronic myeloid leukemia (CML) and its mechanism. METHODS: Cyr61 level in cell culture supernatant was determined by enzyme-linked immunosorbent assay. The expression of Cyr61 and Bcl-xL were measured by real-time PCR and Western blot. Cell apoptosis was analyzed using an Annexin V-APC Kit. Expression of signal pathways related proteins was determined by Western blot. RESULTS: The level of Cyr61 obviously increased in K562G cells (IM resistance to CML cell line K562). Down-regulating the expression of Cyr61 decreased the resistance of K562G cells to IM and promoted IM induced apoptosis. In CML mouse model, down-regulating the expression of Cyr61 could increase the sensitivity of K562G cells to IM. The mechanism studies showed that Cyr61 mediated IM resistance in CML cells was related to the regulation of ERK1/2 pathways and apoptosis related molecule Bcl-xL by Cyr61. CONCLUSION: Cyr61 plays an important role in promoting IM resistance of CML cells. Targeting Cyr61 or its related effectors pathways may be one of the ways to overcome IM resistance of CML cells.

Serum CYR61 as a potential biomarker to improve breast cancer diagnostics.

Purpose: To investigate the role of serum CYR61 as a biomarker for the diagnosis of breast cancer and to analyze the association between serum CYR61 levels and the clinicopathological features in breast cancer patients. Methods: Serum CYR61 was measured in breast cancer patients and healthy controls by ELISA. Results: The serum levels of CYR61 in breast cancer patients were higher than those in healthy controls. The area under the receiver operating characteristic curve for CYR61 was higher than that for carcinoembryonic antigen and carbohydrate antigen 15-3. The increased CYR61 levels were correlated with menopausal status and Ki67 expression. Conclusion: Serum CYR61 might be a novel biomarker to assist the diagnosis and clinicopathological status assessment of breast cancer.

Compare the Diagnostic and Prognostic Value of MLR, NLR and PLR in CRC Patients.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and it is a worldwide challenge. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) had been suggested as markers of CRC, but the role of monocyte-to-lymphocyte ratio (MLR) in CRC patients before surgery and chemotherapy is unclear. The study aimed to compare the diagnosis and prognosis value of MLR, NLR, and PLR in CRC. METHODS: A retrospective study was conducted on 783 patients with histologically confirmed colorectal cancer between 2015 and 2017 in Fujian Medical University Union Hospital. A total of 1,232 healthy age-matched participants were eligible for the study. Receiver-operating characteristic (ROC) analysis was performed to compare the area under the ROC curve (AUC) of MLR, NLR, PLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). Furthermore, chi-squared test was conducted to determine the prognostic values of MLR, NLR, and PLR. RESULTS: The levels of MLR, NLR, and PLR in CRC patients were significantly higher than those in 1,232 healthy participants. The area under the ROC curves (AUCs) of MLR, CEA, PLR, NLR, and CA19-9 were 0.739, 0.726, 0.683, 0.610, and 0.603, respectively. Moreover, the combined marker of CEA + MLR with an AUC of 0.815 acted as a superior diagnostic marker compared to the other combined markers, including the combined marker of CEA + CA19-9. Furthermore, the level of MLR was associated with tumor size (p = 0.001), and a high level of NLR was significantly correlated with pT stage (p = 0.048) and tumor size (p = 0.004). CONCLUSIONS: The present study shows for the first time that MLR rather than NLR and PLR is the better diagnostic marker for colorectal cancer, and NLR may be a better prognostic marker for CRC patients.

Cyr61 mediates oxaliplatin resistance in colorectal cancer cells by regulating Bcl-xL expression.

Although the clinical application of oxaliplatin (L-OHP) has improved the survival of colorectal cancer (CRC) patients, approximately half of patients with CRC fail to achieve good clinical outcomes, indicating resistance to L-OHP therapy. Cysteine-rich protein 61 (Cyr61), a multifunctional extracellular matrix protein, is highly expressed in a variety of tumors; increased Cyr61 expression is known to be closely involved in the chemotherapeutic resistance of many tumors, but its role in the L-OHP resistance of CRC cells has not been studied. In this study, we aimed to investigate the role of Cyr61 in the L-OHP resistance of CRC cells and examine the underlying mechanism. Our findings showed that the mRNA and protein levels of Cyr61 in L-OHP-resistant cells were significantly increased compared with those in nonresistant cells. Knockdown of Cyr61 enhanced the chemosensitivity of L-OHP-resistant cells to L-OHP. Mechanistically, we found that overexpression of Cyr61 decreased L-OHP-induced apoptosis in drug-resistant CRC cells through the regulation of Bcl-xL. Collectively, our results revealed for the first time that Cyr61 plays a crucial role in the resistance of CRC cells to L-OHP and indicated that targeting Cyr61 may be a promising therapeutic strategy to overcome L-OHP resistance in CRC.

An Integrated Bioinformatic Analysis of the S100 Gene Family for the Prognosis of Colorectal Cancer.

BACKGROUND: S100 family genes exclusively encode at least 20 calcium-binding proteins, which possess a wide spectrum of intracellular and extracellular functions in vertebrates. Multiple lines of evidences suggest that dysregulated S100 proteins are associated with human malignancies including colorectal cancer (CRC). However, the diverse expression patterns and prognostic roles of distinct S100 genes in CRC have not been fully elucidated. METHODS: In the current study, we analyzed the mRNA expression levels of S100 family genes and proteins and their associations with the survival of CRC patients using the Oncomine analysis and GEPIA databases. Expressions and mutations of S100 family genes were analyzed using the cBioPortal, and protein-protein interaction (PPI) networks of S100 proteins and their mutation-related coexpressed genes were analyzed using STRING and Cytoscape. RESULTS: We observed that the mRNA expression levels of S100A2, S100A3, S100A9, S100A11, and S100P were higher and the level of S100B was lower in CRC tissues than those in normal colon mucosa. A high S100A10 levels was associated with advanced-stage CRC. Results from GEPIA database showed that highly expressed S100A1 was correlated with worse overall survival (OS) and disease-free survival (DFS) and that overexpressions of S100A2 and S100A11 were associated with poor DFS of CRC, indicating that S100A1, S100A2, and S100A11 are potential prognostic markers. Unexpectedly, most of S100 family genes showed no significant prognostic values in CRC. CONCLUSIONS: Our findings, though still need to be ascertained, offer novel insights into the prognostic implications of the S100 family in CRC and will inspire more clinical trials to explore potential S100-targeted inhibitors for the treatment of CRC.

Utility of red cell distribution width as a diagnostic and prognostic marker in non-small cell lung cancer.

An increasing number of studies have indicated that red blood cell distribution width (RDW) may be a novel biomarker for the diagnosis and prognosis of various malignancies. However, to date, data on the association of RDW with non-small cell lung cancer (NSCLC) are unclear. Our present study aimed to explore the value of RDW in NSCLC patients. A total of 338 NSCLC patients, 109 small cell lung cancer (SCLC) patients, and 302 healthy participants were retrospectively analyzed between January 2016 and December 2018. In the present study, we found that RDW was significantly increased in NSCLC patients. Receiver-operating characteristic (ROC) analysis showed that the area under the ROC curve (AUC) of RDW was 0.753 in discriminating NSCLC patients from healthy participants, the optimal cut-off value of RDW was 12.95, and the specificity and sensitivity were 76.33% and 76.16%, respectively. Further analysis found that RDW can enhance the diagnostic performance of Cyfra21-1 and NSE in discriminating NSCLC patients from healthy participants or SCLC patients. Among NSCLC patients, RDW was significantly correlated with TNM stage, T stage, N stage, M stage, and Cyfra21-1, indicating that RDW may be helpful for predicting the prognosis of NSCLC patients. Our findings suggest that RDW can be used as an auxiliary marker for the diagnosis and prognosis of NSCLC.

Efficacy and safety of iron chelator for transfusion-dependent patients with myelodysplastic syndrome: a meta-analysis.

To systematically evaluate the efficacy and safety of iron chelators for transfusion-dependent patients with MDS. Thirteen cohort studies with 12,990 patients diagnosed with MDS were included in this study. According to m eta-analysis results transfusion-dependent MDS patients with secondary iron overload had a longer (HR = 0.52, 95%CI = 0.43-0.62, P < 0.001). Further subgroup analysis revealed a longer LFS (HR = 0.84, 95%CI = 0.76-0.93, P = 0.001) in MDS patients receiving iron chelators than in MDS patients not receiving iron chelators (HR = 0.52, 95%CI = 0.43-0.62, P < 0.001) and in patients with lower-risk MDS (HR = 0.50, 95%CI = 0.43-0.59, P < 0.001). Subgroup analysis of DFX showed that compared with patients not treated with iron chelators, the group receiving DFX monotherapy had significantly increased OS (HR = 0.43, 95%CI = 0.27-0.69, P < 0.001). In terms of tolerance, meta-analysis of binary variables in CAEs indicated that the occurrence of CAEs was significantly reduced by ICT (RR = 0.64, 95%CI = 0.57-0.71, P < 0.001).