Association Between Intraoperative Noradrenaline Infusion and Outcomes in Older Adult Patients Undergoing Major Non-Cardiac Surgeries: A Retrospective Propensity Score-Matched Cohort Study.

Background: Noradrenaline (NA) is commonly used intraoperatively to prevent fluid overload and maintain hemodynamic stability. Clinical studies provided inconsistent results concerning the effect of NA on postoperative outcomes. As aging is accompanied with various diseases and has the high possibility of the risk for postoperative complications, we hypothesized that intraoperative NA infusion in older adult patients undergoing major non-cardiac surgeries might potentially exert adverse outcomes. Methods: In this retrospective propensity score-matched cohort study, older adult patients undergoing major non-cardiac surgeries were selected, 1837 receiving NA infusion during surgery, and 1072 not receiving NA. The propensity score matching was conducted with a 1:1 ratio and 1072 patients were included in each group. The primary outcomes were postoperative in-hospital mortality and complications. Results: Intraoperative NA administration reduced postoperative urinary tract infection (OR:0.124, 95% CI:0.016-0.995), and had no effect on other postoperative complications and mortality, it reduced intraoperative crystalloid infusion (OR:0.999, 95% CI:0.999-0.999), blood loss (OR: 0.998, 95% CI: 0.998-0.999), transfusion (OR:0.327, 95% CI: 0.218-0.490), but increased intraoperative lactate production (OR:1.354, 95% CI:1.051-1.744), and hospital stay (OR:1.019, 95% CI:1.008-1.029). Conclusion: Intraoperative noradrenaline administration reduces postoperative urinary tract infection, and does not increase other postoperative complications and mortality, and can be safely used in older adult patients undergoing major non-cardiac surgeries.

Resistance-driven innovations in the discovery of bactericides: novel triclosan derivatives decorating isopropanolamine moiety as promising anti-biofilm agents against destructive plant bacterial diseases.

BACKGROUND: Controlling bacterial infections in plants is a major challenge owing to the appearance of resistant strains. As a physical barrier, the bacterial biofilm helps bacterial infections acquire drug resistance by enabling bacteria to accommodate complex and volatile environmental conditions and avoid bactericidal effects. Thus, developing new antibacterial agents with antibiofilm potency is imperative. RESULTS: A series of simple triclosan derivatives containing isopropanolamine moiety were elaborately designed and assessed for their antibacterial behavior. Bioassay results showed that some title compounds had excellent bioactivity against three destructive bacteria Xanthomonas oryzae pv. oryzae (Xoo), Xanthomonas axonopodis pv. citri (Xac) and Pseudomonas syringae pv. actinidiae (Psa). Notably, compound C8 displayed high bioactivities toward Xoo and Xac, with EC50 values were 0.34 and 2.11 µg mL-1 , respectively. In vivo trials revealed that compound C8 exhibited excellent protective activities against rice bacterial blight and citrus bacterial canker at 200 µg mL-1 , with control effectivenesses of 49.57% and 85.60%, respectively. Compound A4 had remarkably inhibitory activity toward Psa, with an EC50 value of 2.63 µg mL-1 , and demonstrated outstanding protective activity with a value of 77.23% against Psa in vivo. Antibacterial mechanisms indicated that compound C8 dose-dependently prevented biofilm formation and extracellular polysaccharide production. C8 also significantly weakened the motility and pathogenicity of Xoo. CONCLUSION: This study contributes to the development and excavation of novel bactericidal candidates with broad-spectrum antibacterial activity by targeting bacterial biofilm to control refractory plant bacterial diseases. © 2023 Society of Chemical Industry.

Long noncoding RNA H19 regulates degeneration and regeneration of injured peripheral nerves.

Our previous studies have shown that long noncoding RNA (lncRNA) H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration, and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons. However, the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear. In this study, we established a Sprague-Dawley rat model of sciatic nerve transection injury. We performed in situ hybridization and found that at 4-7 days after sciatic nerve injury, lncRNA H19 was highly expressed. At 14 days before injury, adeno-associated virus was intrathecally injected into the L4-L5 foramina to disrupt or overexpress lncRNA H19. After overexpression of lncRNA H19, the growth of newly formed axons from the sciatic nerve was inhibited, whereas myelination was enhanced. Then, we performed gait analysis and thermal pain analysis to evaluate rat behavior. We found that lncRNA H19 overexpression delayed the recovery of rat behavior function, whereas interfering with lncRNA H19 expression improved functional recovery. Finally, we examined the expression of lncRNA H19 downstream target SEMA6D, and found that after lncRNA H19 overexpression, the SEMA6D protein level was increased. These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves. This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.

Development and Validation of a Nomogram for Predicting Postoperative Pulmonary Infection in Patients Undergoing Lung Surgery.

OBJECTIVES: To develop and validate a nomogram for predicting postoperative pulmonary infection (PPI) in patients undergoing lung surgery. DESIGN: Single-center retrospective cohort analysis. SETTING: A university-affiliated cancer hospital PARTICIPANTS: A total of 1,501 adult patients who underwent lung surgery from January 2018 to December 2020. INTERVENTIONS: Observation for PPI within 7 days after lung surgery. MEASUREMENTS AND MAIN RESULTS: A complete set of demographics, preoperative variables, and postoperative follow-up data was recorded. The primary outcome was PPI; a total of 125 (8.3%) out of 1,501 patients developed PPI. The variables with p < 0.1 in univariate logistic regression were included in the multivariate regression, and multivariate logistic regression analysis showed that surgical procedure, surgical duration, the inspired fraction of oxygen in one-lung ventilation, and postoperative pain were independent risk factors for PPI. A nomogram based on these factors was constructed in the development cohort (area under the curve: 0.794, 95% CI 0.744-0.845) and validated in the validation cohort (area under the curve: 0.849, 95% CI 0.786-0.912). The calibration slope was 1 in the development and validation cohorts. Decision curve analysis indicated that when the threshold probability was within a range of 0.02-to-0.58 and 0.02-to-0.42 for the development and validation cohorts, respectively, the nomogram model could provide a clinical net benefit. CONCLUSIONS: The authors developed and validated a nomogram for predicting PPI in patients undergoing lung surgery. The prediction model can predict the development of PPI and identify high-risk groups.

Relationship between morning peak phenomenon and early renal injury NGAL in H-type hypertension.

PURPOSE: To investigate the relationship between morning blood pressure surge (MBPS) and neutrophilgelatinase associated lipocalin (NGAL) in patients with H-type hypertension. MATERIALS AND METHODS: A total of 224 patients with diagnosed H-type hypertension [homocysteine (Hcy)≧10umol/L] were selected and underwent 24-hour ambulatory blood pressure monitoring (ABPM). In the morning peak group (115 cases), NGAL and serum cystatin C levels, ß2-microglobulin levels were detected in each group, and general biochemical indicators were also detected. RESULTS: There was no significant difference in the course of hypertension, age, blood glucose, blood lipids, Hcy, BUN, Cr, and UA between the two groups (p > 0.05). CysC, ß2-MG were higher than those in the nonmorning peak group, and the difference was statistically significant (p < 0.05).; Pearson correlation analysis showed that NGAL was moderately and highly correlated with CysC, systolic blood pressure morning peak, ß2-MG, and high (p < 0.05), low-density lipoprotein (LDL-C), and Hcy were lowly correlated (p < 0.05).) and morning peak diastolic blood pressure (p > 0.05); multiple linear stepwise regression analysis indicated that morning peak systolic blood pressure, CysC,ß2-MG, and FBG were the risk factors for NGAL. CONCLUSION: The morning peak of systolic blood pressure in H-type hypertension is an important factor causing kidney injury. Paying attention to the ambulatory blood pressure monitoring and the control of morning peak blood pressure in patients with H-type hypertension, and early screening of NGAL has important clinical significance for the early prevention and treatment of renal injury in patients with H-type hypertension. PLAIN LANGUAGE SUMMARYThe morning peak of blood pressure is closely related to target organ damage.There are few studies on the relationship between morning peak phenomenon and renal damage in patients with H-type hypertension at home and abroad.We investigated the relationship between MBPS and NGAL in H-type hypertensive patients with BUN, Cr and UA in the normal range to provide a clinical basis for early renal protection in hypertensive patients.

FOXF2 oppositely regulates stemness in luminal and basal-like breast cancer cells through the Wnt/beta-catenin pathway.

The stemness of cancer cells contributes to tumorigenesis, the heterogeneity of malignancies, cancer metastasis, and therapeutic resistance. However, the roles and regulatory mechanisms maintaining stemness among breast cancer subtypes remain elusive. Our previous studies have demonstrated that ectopic expression and dynamic alteration of the mesenchymal transcription factor forkhead box F2 (FOXF2) differentially regulates breast cancer progression and metastasis organotropism in a cell subtype-specific manner. Here, we reveal the underlying mechanism by which FOXF2 enhances stemness in luminal breast cancer cells but suppresses that in basal-like breast cancer (BLBC) cells. We show that luminal breast cancer and BLBC cells with FOXF2-regulated stemness exhibit partial mesenchymal stem cell properties that toward osteogenic differentiation and myogenic differentiation, respectively. Furthermore, we show that FOXF2 activates the Wnt signaling pathway in luminal breast cancer cells but represses this pathway in BLBC cells by recruiting nuclear receptor coactivator 3 (NCoA3) and nuclear receptor corepressor 1 (NCoR1) to the promoters of Wnt family member 2B (WNT2B) and frizzled class receptor 1 (FZD1) genes to activate and repress their transcription, respectively. We propose that targeting the Wnt signaling pathway is a promising strategy for the treatment of breast cancers with dysregulated expression of FOXF2.

[Clinical Significance of EBV-DNA Copy Number in EBV Positive Lymphoma Patients].

OBJECTIVE: To investigate the effect of EBV-DNA copy number on the prognosis of patients with EBV positive lymphoma. METHODS: Clinical data of 109 patients diagnosed as EBV positive lymphoma in Tianjin Medical University Cancer Institute and Hospital from January 2010 to January 2020 were enrolled and analyzed retrospectively. Kaplan-Meier analysis was used for survival analysis, Log-rank was used to compare the clinical characteristics between the patients in different groups, and Cox regression was used for multivariate analysis. RESULTS: Among the 109 patients with EBV-positive lymphoma, the medium age were 56 (range 15 to 83) years old. 29 patients at Ann Arbor stage I-II while 80 patients at stage III-IV. The average value of EBV-DNA was 1 023 510 IU/ml, 7 patients were higher than the average value, while 102 patients were lower. KM survival analysis showed that OS and PFS in patients with EBV-DNA above average level were shorter than those in patients with EBV-DNA below average level (OS: P=0.048, PFS: P=0.001), EBV-DNA copy number was a factor affecting the prognosis of patients. In addition, LDH level showed positive correlation with EBV-DNA copy number (r=0.650), which was also one of the factors affecting OS (P=0.053). CONCLUSION: EBV-DNA copy number and LDH level can influence the prognosis of EBV positive lymphoma patients. Therefore, detection of EBV-DNA copy number in peripheral blood is important for evaluate the prognosis the patients.

FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-ß and miR-182-5p.

The mesenchymal transcription factor forkhead box F2 (FOXF2) is a critical regulator of embryogenesis and tissue homeostasis. Our previous studies demonstrated that FOXF2 is ectopically expressed in basal-like breast cancer (BLBC) cells and that FOXF2 deficiency promotes the epithelial-mesenchymal transition and aggressiveness of BLBC cells. In this study, we found that FOXF2 controls transforming growth factor-beta (TGF-ß)/SMAD signaling pathway activation through transrepression of TGF-ß-coding genes in BLBC cells. FOXF2-deficient BLBC cells adopt a myofibroblast-/cancer-associated fibroblast (CAF)-like phenotype, and tend to metastasize to visceral organs by increasing autocrine TGF-ß signaling and conferring aggressiveness to neighboring cells by increasing paracrine TGF-ß signaling. In turn, TGF-ß silences FOXF2 expression through upregulating miR-182-5p, a posttranscriptional regulator of FOXF2 and inducer of metastasis. In addition to mediating a reciprocal repression loop between FOXF2 and TGF-ß through direct transrepression by SMAD3, miR-182-5p forms a reciprocal repression loop with FOXF2 that directly transrepresses MIR182 expression. Therefore, FOXF2 deficiency accelerates the visceral metastasis of BLBC through unrestricted increases in autocrine and paracrine TGF-ß signaling, and miR-182-5p expression. Our findings provide novel mechanisms underlying the roles of TGF-ß, miR-182-5p, and FOXF2 in accelerating BLBC dissemination and metastasis, and may facilitate the development of therapeutic strategies for aggressive BLBC.

FOXF2 reprograms breast cancer cells into bone metastasis seeds.

Bone metastases occur in most advanced breast cancer patients and cause serious skeletal-related complications. The mechanisms by which bone metastasis seeds develop in primary tumors and specifically colonize the bone remain to be elucidated. Here, we show that forkhead box F2 (FOXF2) functions as a master transcription factor for reprogramming cancer cells into an osteomimetic phenotype by pleiotropic transactivation of the BMP4/SMAD1 signaling pathway and bone-related genes that are expressed at early stages of bone differentiation. The epithelial-to-osteomimicry transition regulated by FOXF2 confers a tendency on cancer cells to metastasize to bone which leads to osteolytic bone lesions. The BMP antagonist Noggin significantly inhibits FOXF2-driven osteolytic bone metastasis of breast cancer cells. Thus, targeting the FOXF2-BMP/SMAD axis might be a promising therapeutic strategy to manage bone metastasis. The role of FOXF2 in transactivating bone-related genes implies a biological function of FOXF2 in regulating bone development and remodeling.

Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

FOXF2 and FOXQ1, forkhead box transcription factor superfamily members, are encoded by neighboring genes located on human chromosome 6p25.3 and play opposite roles in epithelial-mesenchymal transition (EMT) and metastasis in basal-like breast cancer (BLBC). However, the relationship between FOXF2 and FOXQ1 in cancer remains unknown. Here, we found mutual transcriptional repression between FOXF2 and FOXQ1, and the reciprocal negative feedback loop controlled EMT, aggressiveness, and chemoresistance in BLBC cells. We further demonstrated that FOXF2 recruited nuclear receptor corepressor 1 and histone deacetylase 3 to the FOXQ1 promoter to inhibit its transcription in BLBC cells, but FOXQ1 did not exert such an effect on FOXF2. Our findings reveal novel mechanisms underlying the determination of BLBC aggressiveness and the transrepressive function of FOXF2 in a basal-like cell subtype-specific manner. Therefore, blocking the vicious cycle of the abnormal reciprocal feedback loop between FOXF2 and FOXQ1 to induce cell differentiation and restore tissue homeostasis is a promising strategy for the treatment of aggressive BLBC.-Kang, L.-J., Yu, Z.-H., Cai, J., He, R., Lu, J.-T., Hou, C., Wang, Q.-S., Li, X.-Q., Zhang, R., Feng, Y.-M. Reciprocal transrepression between FOXF2 and FOXQ1 controls basal-like breast cancer aggressiveness.

FOXF2 deficiency permits basal-like breast cancer cells to form lymphangiogenic mimicry by enhancing the response of VEGF-C/VEGFR3 signaling pathway.

Lymphatic metastasis is the main route of breast cancer metastasis. It is known that lymphangiogenesis facilitates lymphatic metastasis through vascular endothelial growth factor-C (VEGF-C)/VEGF receptor 3 (VEGFR3) pathway-linked interactions between the tumor and its microenvironment. Here, we report a novel mechanism of lymphatic metastasis by which aggressive basal-like breast cancer (BLBC) cells form lymphatic vessel-like structures that are identified by the positive expression of lymphatic endothelial cell markers lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), podoplanin, and VEGFR3, and termed as lymphangiogenic mimicry (LM), for the first time. Our clinical evidence and experimental data in vivo and in vitro revealed that forkhead box F2 (FOXF2) deficiency promotes the lymphatic metastasis of BLBC by conferring a lymphangiogenic mimetic feature upon cancer cells through directly activating VEGFR3 transcription. The fact that FOXF2 controls the activation of the VEGF-C/VEGFR3 signaling pathway in BLBC cells provides potential molecular diagnostic and therapeutic strategies for lymphatic metastasis in BLBC patients.

Dual function of MAZ mediated by FOXF2 in basal-like breast cancer: Promotion of proliferation and suppression of progression.

Myc-associated zinc finger protein (MAZ) is a transcription factor with C2H2-type zinc-finger motifs that can bind GC-rich cis-elements. MAZ activates the transcription of some cancer-related genes and represses that of others, suggesting that changes in MAZ expression may play different roles in the development and progression of different types or subtypes of cancers depending on its target genes. However, the functions and mechanisms of MAZ in regulating the carcinogenesis and progression of breast cancer have remained unclear. In the current study, we show that MAZ performs dual function in basal-like breast cancer (BLBC): suppression of aggressiveness and promotion of proliferation. Forkhead box F2 (FOXF2) is a novel transcription target of MAZ and mediates the functions of MAZ. The MAZ mRNA level, particularly in combination with the FOXF2 mRNA level, may serve as a prognostic marker for BLBC patients. Our results indicate that the dual function of the MAZ-FOXF2 axis reflect the pleiotropic nature of multifunctional transcription factors in regulating the different stages of cancer development and progression, which could lead to the complexity of cancer diagnosis and treatment.

Breast cancer cells obtain an osteomimetic feature via epithelial-mesenchymal transition that have undergone BMP2/RUNX2 signaling pathway induction.

Bone is one of the most common organs of breast cancer metastasis. Cancer cells that mimic osteoblasts by expressing bone matrix proteins and factors have a higher likelihood of metastasizing to bone. However, the molecular mechanisms of osteomimicry formation of cancer cells remain undefined. Herein, we identified a set of bone-related genes (BRGs) that are ectopically co-expressed in primary breast cancer tissues and determined that osteomimetic feature is obtained due to the osteoblast-like transformation of epithelial breast cancer cells that have undergone epithelial-mesenchymal transition (EMT) followed by bone morphogenetic protein-2 (BMP2) stimulation. Furthermore, we demonstrated that breast cancer cells that transformed into osteoblast-like cells with high expression of BRGs showed enhanced chemotaxis, adhesion, proliferation and multidrug resistance in an osteoblast-mimic bone microenvironment in vitro. During these processes, runt-related transcription factor 2 (RUNX2) functioned as a master mediator by suppressing or activating the transcription of BRGs that underlie the dynamic antagonism between the TGF-ß/SMAD and BMP/SMAD signaling pathways in breast cancer cells. Our findings suggest a novel mechanism of osteomimicry formation that arises in primary breast tumors, which may explain the propensity of breast cancer to metastasize to the skeleton and contribute to potential strategies for predicting and targeting breast cancer bone metastasis and multidrug resistance.

RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization.

Runt-related transcription factor 2 (RUNX2) is regarded as an important contributor to breast cancer bone metastasis. However, previous studies did not provide direct clinical evidence for a role of RUNX2 in bone-specific metastasis in breast cancer, and the mechanism of RUNX2 in cancer cell recruitment and adhesion to the bone remains unclear. In this study, we showed that RUNX2 expression is positively correlated with the risk of bone-specific metastasis in lymph node-negative breast cancer patients. Then, we identified ITGA5 as a transcriptional target of RUNX2 from multiple candidate genes encoding adhesion molecules or chemokine receptors. We further provided experimental and clinical evidence that RUNX2, in an integrin α5-dependent manner, promotes the attraction and adhesion of breast cancer cells to the bone and confers cancer cell survival and bone colonization advantages. Overall, our findings clarify an adhesion-dependent mechanism of RUNX2 for the osteotropism and bone colonization of breast cancer cells and implicate RUNX2 and integrin α5 as potential molecular markers for the prediction of bone metastasis and therapeutic targets for the treatment of breast cancer bone metastasis.

FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer.

Forkhead box (FOX) F2 and FOXC2 belong to the FOX transcription factor superfamily. FOXC2 is recognized as an inducer of epithelial-mesenchymal transition (EMT), and its overexpression promotes basal-like breast cancer (BLBC) metastasis. Our previous study demonstrated that FOXF2 functions as an EMT suppressor and that FOXF2 deficiency promotes BLBC metastasis. However, the relationship between the opposite EMT-related transcription factors FOXF2 and FOXC2 remains unknown. Here, we found that FOXF2 directly targets FOXC2 to negatively regulate FOXC2 transcription in BLBC cells. Functionally, we observed that FOXC2 mediates the FOXF2-regulated EMT phenotype, aggressive behavior, and multiple chemotherapy drug resistance of BLBC cells. Additionally, we detected a significant negative correlation between the FOXF2 and FOXC2 mRNA levels in triple-negative breast cancer (TNBC) tissues. TNBC patients in the FOXF2high/FOXC2low and FOXF2low/FOXC2high groups exhibited the best and worst disease-free survival (DFS), respectively, whereas the patients in the FOXF2high/FOXC2high and FOXF2low/FOXC2low groups exhibited moderate DFS. In summary, we found that FOXF2 transcriptionally targets FOXC2 and suppresses EMT and multidrug resistance by negatively regulating the transcription of FOXC2 in BLBC cells. The combined expression levels of FOXF2 and FOXC2 mRNA might serve as an effective prognostic indicator and could guide tailored therapy for TNBC or BLBC patients.

DNA Methylation Affects the SP1-regulated Transcription of FOXF2 in Breast Cancer Cells.

FOXF2 (forkhead box F2) is a mesenchyme-specific transcription factor that plays a critical role in tissue homeostasis through the maintenance of epithelial polarity. In a previous study, we demonstrated that FOXF2 is specifically expressed in basal-like breast cancer (BLBC) cells and functions as an epithelial-mesenchymal transition suppressor. FOXF2 deficiency enhances the metastatic ability of BLBC cells through activation of the epithelial-mesenchymal transition program, but reduces cell proliferation. In this study, we demonstrate that CpG island methylation of the FOXF2 proximal promoter region is involved in the regulatory mechanism of the subtype-specific expression of FOXF2 in breast cancer cells. DNMT1, DNMT3A, and DNMT3B commonly or individually contributed to this DNA methylation in different breast cancer cells. SP1 regulated the transcriptional activity of FOXF2 through direct binding to the proximal promoter region, whereas this binding was abrogated through DNA methylation. FOXF2 mediated the SP1-regulated suppression of progression and promotion of proliferation of non-methylated BLBC cells. Thus, we conclude that the subtype-specific expression and function of FOXF2 in breast cancer cells are regulated through the combined effects of DNA methylation and SP1 transcriptional regulation.

ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFß Signaling Pathway.

Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin ß-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFß signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer.

FOXF2 deficiency promotes epithelial-mesenchymal transition and metastasis of basal-like breast cancer.

INTRODUCTION: Our previous clinical study demonstrated that the under-expression of FOXF2 is associated with early-onset metastasis and poor prognosis of patients with triple-negative breast cancer. In this study, we further characterized the role of FOXF2 in metastasis of basal-like breast cancer (BLBC) and underlying molecular mechanisms. METHODS: RT-qPCR, immunoblot, immunofluorescence and immunohistochemistry were performed to assess the expression of genes and proteins in cell lines and tissues. A series of in vitro and in vivo assays was performed in the cells with RNAi-mediated knockdown or overexpression to elucidate the function and transcriptional regulatory role of FOXF2 in breast cancer. RESULTS: We found that FOXF2 was specifically expressed in most basal-like breast cells. FOXF2 deficiency enhanced the metastatic ability of BLBC cells in vitro and in vivo. Additionally, FOXF2 deficiency induced the epithelial-mesenchymal transition (EMT) of basal-like breast cells. Furthermore, we identified that TWIST1 is a transcriptional target of FOXF2. TWIST1 was negatively regulated by FOXF2 and mediated the FOXF2-regulated EMT phenotype of basal-like breast cells and aggressive property of BLBC. CONCLUSIONS: FOXF2 is a novel EMT-suppressing transcription factor in BLBC. FOXF2 deficiency enhances metastatic ability of BLBC cells by activating the EMT program through upregulating the transcription of TWIST1.

Inhibition of KIF22 suppresses cancer cell proliferation by delaying mitotic exit through upregulating CDC25C expression.

KIF22 is a microtubule-dependent molecular motor protein with DNA-binding capacity. It is well known that KIF22 plays a critical role in cell mitosis as a motor protein; however, the role of altered KIF22 expression and its transcriptional regulatory function in cancer development have not yet been defined. This study showed that KIF22 was overexpressed in human cancer tissues, and inhibition of KIF22 significantly led to accumulation of cells in the G2/M phases, resulting in suppression of cancer cell proliferation. The investigation of the molecular mechanisms demonstrated that cell division cycle 25C (CDC25C) is a direct transcriptional target of KIF22, and inhibition of KIF22 increased CDC25C expression and cyclin-dependent kinase 1 (CDK1) activity, resulting in delayed mitotic exit. Phosphorylation of KIF22 was required for its transcriptional regulatory function and the reduction of CDK1 activity. Thus, we conclude that inhibition of KIF22 suppresses cancer cell proliferation by delaying mitotic exit through the transcriptional upregulation of CDC25C.

The GSTP1 105Val allele increases breast cancer risk and aggressiveness but enhances response to cyclophosphamide chemotherapy in North China.

The glutathione-S-transferase (GST) family contributes to the inactivation of various toxic compounds formed as secondary metabolites during oxidative stress. GSTP1 accounts for the majority of the GST family enzymatic activity, and the activity of GSTP1 enzyme can be altered by the presence of the Ile105Val polymorphism. In this study, we examined the polymorphic frequency of GSTP1 Ile105Val genotype in 920 breast cancer patients and 783 healthy controls in women of North China. Results showed that GSTP1 105Val allele (Ile/Val and Val/Val) was associated with a higher breast cancer risk (OR = 1.38, 95% CI: 1.14-1.69; P = 0.001) and more aggressive tumors with histological grade III (OR = 1.15, 95% CI: 1.05-1.26; P = 0.001), lymph node metastases (OR = 2.35, 95% CI: 1.72-3.21; P < 0.001), as well as ER negative (OR = 1.77, 95% CI: 1.31-2.39; P < 0.001) than those carrying the Ile/Ile allele. However, the patients with the GSTP1 105Val genotype had a better disease free survival after cyclophosphamide (CTX)-based chemotherapy than those with Ile/Ile (HR = 0.77, 95% CI: 0.45-0.91; P < 0.001). Furthermore, in vitro cellular experiments demonstrated that breast cancer cells with the GSTP1 105Val allele were significantly more sensitive to CTX-induced proliferation inhibition. Thus, we conclude that the GSTP1 105Val allele increases breast cancer risk and aggressiveness and enhance response to CTX-based chemotherapy in women of North China. Detection of the GSTP1 Ile105Val genotype may help screen for high-risk populations and direct individualized therapy.