Quaternized Amphiphilic Block Copolymers as Antimicrobial Agents

In this study, a novel polystyrene-block-quaternized polyisoprene amphipathic block copolymer (PS-b-PIN) is derived from anionic polymerization. Quaternized polymers are prepared through post-quaternization on a functionalized polymer side chain. Moreover, the antibacterial activity of quaternized polymers without red blood cell (RBCs) hemolysis can be controlled by block composition, side chain length, and polymer morphology. The solvent environment is highly related to the polymer morphology, forming micelles or other structures. The polymersome formation would decrease the hemolysis and increase the electron density or quaternized groups density as previous research and our experiment revealed. Herein, the PS-b-PIN with N,N-dimethyldodecylamine as side chain would form a polymersome structure in the aqueous solution to display the best inhibiting bacterial growth efficiency without hemolytic effect. Therefore, the different single-chain quaternized groups play an important role in the antibacterial action, and act as a controllable factor

Silencing DNA Polymerase β Induces Aneuploidy as a Biomarker of Poor Prognosis in Oral Squamous Cell Cancer

Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis. The treatment strategies are diverse, including surgery, radiotherapy and chemotherapy. Despite multimodality treatment, the response rate is unsatisfactory. DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation. Therefore, focusing on DNA repair and genetic instability interactions could be a potential target for improving the outcomes of OSCC patients. DNA polymerase-β (POLB) is an important enzyme in base excision repair and contributes to gene instability, leading to tumorigenesis and cancer metastasis. The aim of our study was to confirm POLB regulates the growth of OSCC cells through modulation of cell cycle and chromosomal instability. We analyzed a tissue array from 133 OSCC patients and discovered that low POLB expression was associated with advanced tumor stage and poor overall survival. In multivariate Cox proportional hazards regression analysis, low POLB expression and advanced lymph node status were significantly associated with poor survival. By performing in vitro studies on model cell lines, we demonstrated that POLB silencing regulated cell cycles, exacerbated mitotic abnormalities and enhanced cell proliferation. After POLB depletion, OSCC cells showed chromosomal instability and aneuploidy. Thus, POLB is an important maintainer of karyotypic stability in OSCC cells

FAK is Required for Tumor Metastasis-Related Fluid Microenvironment in Triple-Negative Breast Cancer

Cancer cell metastasis is the main cause of death in patients with cancer. Many studies have investigated the biochemical factors that affect metastasis; however, the role of physical factors such as fluid shear stress (FSS) in tumorigenesis and metastasis have been less investigated. Triple-negative breast cancer (TNBC) has a higher incidence of lymph node invasion and distant metastasis than other subtypes of breast cancer. In this study, we investigated the influence of FSS in regulating the malignant behavior of TNBC cells. Our data demonstrate that low FSS promotes cell migration, invasion, and drug resistance, while high FSS has the opposite results; additionally, we found that these phenomena were regulated through focal adhesion kinase (FAK). Using immunohistochemistry staining, we show that FAK levels correlate with the nodal stage and that FAK is a significant independent predictor of overall survival in patients. Altogether, these data implicate FAK as a fluid mechano-sensor that regulates the cell motility induced by FSS and provide a strong rationale for cancer treatments that combine the use of anti-cancer drugs and strategies to modulate tumor interstitial fluid flow

FAK Regulates VEGFR2 Expression and Promotes Angiogenesis in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains a significant clinical challenge because of its high vascularity and metastatic and recurrent rates. Tumor angiogenesis is considered an important mediator in the regulation of tumor cell survival and metastasis in TNBC. Angiogenesis is induced by the binding of vascular endothelial growth factor to vascular endothelial growth factor receptor 2 (VEGFR2). Focal adhesion kinase (FAK) plays an important role in regulating various cell functions in normal and cancer cells. Previous studies have focused on investigating the function of endothelial FAK in tumor cell angiogenesis. However, the association between tumor FAK and VEGFR2 in tumor angiogenesis and the possible mechanisms of this remain unclear. In this study, we used a public database and human specimens to examine the association between FAK and VEGFR2. At the same time, we verified the association between FAK and VEGFR2 through several experimental methods, such as quantitative real-time polymerase chain reaction, Western blotting, and next-generation sequencing. In addition, we used the endothelial cell model, zebrafish, and xenograft animal models to investigate the role of FAK in TNBC angiogenesis. We found that FAK and VEGFR2 were positively correlated in patients with TNBC. VEGFR2 and several other angiogenesis-related genes were regulated by FAK. In addition, FAK regulated VEGFR2 and VEGF protein expression in TNBC cells. Functional assays showed that FAK knockdown inhibited endothelial tube formation and zebrafish angiogenesis. An animal model showed that FAK inhibitors could suppress tumor growth and tumor vascular formation. FAK promotes angiogenesis in TNBC cells by regulating VEGFR2 expression. Therefore, targeting FAK could be another antiangiogenic strategy for TNBC treatment

β1 Integrin as a Prognostic and Predictive Marker in Triple-Negative Breast Cancer

Triple negative breast cancer (TNBC) displays higher risk of recurrence and distant metastasis. Due to absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), TNBC lacks clinically established targeted therapies. Therefore, understanding of the mechanism underlying the aggressive behaviors of TNBC is required for the design of individualized strategies and the elongation of overall survival duration. Here, we supported a positive correlation between β1 integrin and malignant behaviors such as cell migration, invasion, and drug resistance. We found that silencing of β1 integrin inhibited cell migration, invasion, and increased the sensitivity to anti-cancer drug. In contrast, activation of β1 integrin increased cell migration, invasion, and decreased the sensitivity to anti-cancer drug. Furthermore, we found that silencing of β1 integrin abolished Focal adhesion kinese (FAK) mediated cell survival. Overexpression of FAK could restore cisplatin-induced apoptosis in β1 integrin-depleted cells. Consistent to in vitro data, β1 integrin expression was also positively correlated with FAK (p = 0.031) in clinical tissue. More importantly, β1 integrin expression was significantly correlated with patient outcome. In summary, our study indicated that β1 integrin could regulate TNBC cells migration, invasion, drug sensitivity, and be a potential prognostic biomarker in TNBC patient survival

Combination of FAK inhibitor and cytokine-induced killer cell therapy: An alternative therapeutic strategy for patients with triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by the loss of expression of several biomarkers, which limits treatment strategies for the disease. In recent years, immunotherapy has shown promising results in the treatment of various tumors. Emerging evidence demonstrated that TNBC is an immune-activated cancer, suggesting that immunotherapy could be a feasible treatment option for TNBC. Cytokine-induced killer (CIK) cell therapy is considered as a potential treatment for cancer treatment. However, it is still not approved as a standard treatment in the clinical setting. Our previous study demonstrated that focal adhesion kinase (FAK) plays important role in regulating the sensitivity of TNBC cells to CIK cells. In this study, we further verify the role of FAK in regulating the immune response in vivo. Our in vitro study indicated that knockdown of FAK in TNBC cells or treat with the FAK inhibitor followed by co-culture with CIK cells induced more cell death than CIK cells treatment only. RNA-seq analysis indicated that suppression of FAK could affect several immune-related gene expressions in TNBC cells that affects the immune response in the tumor microenvironment of TNBC cells. The combination of FAK inhibitor and CIK cells significantly suppressed tumor growth than the treatment of FAK inhibitor or CIK cells alone in vivo. Our findings provide new insights into the cytotoxic effect of CIK cell therapy in TNBC treatment and indicate that the combination of CIK cell therapy with FAK inhibitors may be an alternative therapeutic strategy for patients with TNBC

Correction: Pan et al. Impact of FAK Expression on the Cytotoxic Effects of CIK Therapy in Triple-Negative Breast Cancer. Cancers 2020, 12, 94

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