SOSTDC1 Nuclear Translocation Facilitates BTIC Maintenance and CHD1-Mediated HR Repair to Promote Tumor Progression and Olaparib Resistance in TNBC.

Breast tumor-initiating cells (BTICs) of triple-negative breast cancer (TNBC) tissues actively repair DNA and are resistant to treatments including chemotherapy, radiotherapy, and targeted therapy. Herein, it is found that a previously reported secreted protein, sclerostin domain containing 1 (SOSTDC1), is abundantly expressed in BTICs of TNBC cells and positively correlated with a poor patient prognosis. SOSTDC1 knockdown impairs homologous recombination (HR) repair, BTIC maintenance, and sensitized bulk cells and BTICs to Olaparib. Mechanistically, following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin-α dependent manner. Nuclear SOSTDC1 interacts with the N-terminus of the nucleoprotein, chromatin helicase DNA-binding factor (CHD1), to promote HR repair and BTIC maintenance. Furthermore, nuclear SOSTDC1 bound to ß-transducin repeat-containing protein (ß-TrCP) binding motifs of CHD1 is found, thereby blocking the ß-TrCP-CHD1 interaction and inhibiting ß-TrCP-mediated CHD1 ubiquitination and degradation. Collectively, these findings identify a novel nuclear SOSTDC1 pathway in regulating HR repair and BTIC maintenance, providing insight into the TNBC therapeutic strategies.

Autophagy in cancer immunotherapy: Perspective on immune evasion and cell death interactions.

Both the innate and adaptive immune systems work together to produce immunity. Cancer immunotherapy is a novel approach to tumor suppression that has arisen in response to the ineffectiveness of traditional treatments like radiation and chemotherapy. On the other hand, immune evasion can diminish immunotherapy's efficacy. There has been a lot of focus in recent years on autophagy and other underlying mechanisms that impact the possibility of cancer immunotherapy. The primary feature of autophagy is the synthesis of autophagosomes, which engulf cytoplasmic components and destroy them by lysosomal degradation. The planned cell death mechanism known as autophagy can have opposite effects on carcinogenesis, either increasing or decreasing it. It is autophagy's job to maintain the balance and proper functioning of immune cells like B cells, T cells, and others. In addition, autophagy controls whether macrophages adopt the immunomodulatory M1 or M2 phenotype. The ability of autophagy to control the innate and adaptive immune systems is noteworthy. Interleukins and chemokines are immunological checkpoint chemicals that autophagy regulates. Reducing antigen presentation to induce immunological tolerance is another mechanism by which autophagy promotes cancer survival. Therefore, targeting autophagy is of importance for enhancing potential of cancer immunotherapy.

Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1.

Tumor-resident microbiota in breast cancer promotes cancer initiation and malignant progression. However, targeting microbiota to improve the effects of breast cancer therapy has not been investigated in detail. Here, we evaluated the microbiota composition of breast tumors and found that enterotoxigenic Bacteroides fragilis (ETBF) was highly enriched in the tumors of patients who did not respond to taxane-based neoadjuvant chemotherapy. ETBF, albeit at low biomass, secreted the toxic protein BFT-1 to promote breast cancer cell stemness and chemoresistance. Mechanistic studies showed that BFT-1 directly bound to NOD1 and stabilized NOD1 protein. NOD1 was highly expressed on ALDH+ breast cancer stem cells (BCSCs) and cooperated with GAK to phosphorylate NUMB and promote its lysosomal degradation, thereby activating the NOTCH1-HEY1 signaling pathway to increase BCSCs. NOD1 inhibition and ETBF clearance increase the chemosensitivity of breast cancer by impairing BCSCs.

A Comprehensive Prognostic and Immune Infiltration Analysis of RBM4 in Pan-Cancer.

BACKGROUND: Aberrant splicing has been closely associated with human cancer, though the precise underlying mechanisms linking the two remain not fully understood. Investigating the role of splicing factors in cancer progression may aid in the development of targeted therapies for dysregulated splicing, thereby opening up new avenues for cancer treatment. RNA-binding motif 4 (RBM4) has been identified as a critical participant in the condensin II complex, which is involved in chromosome condensation and stabilization during mitosis. Its significance in tumors is currently gaining attention. The genetic characteristics of RBM4 suggest its potential to elucidate the malignant progression of tumors in a broader context, encompassing various types of cancer, known as pan-cancer. METHODS: This study aims to comprehensively explore the potential function of RBM4 in pan-cancer by leveraging existing databases such as The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). RESULTS: RBM4 is found to be overexpressed in almost all tumors and exhibits significant prognostic and diagnostic efficacy. The correlation between RBM4 and immune signatures, including immune cell infiltration and immune checkpoint genes, indicates that RBM4 could serve as a guiding factor for immunotherapy. CONCLUSIONS: As a member of the pan-oncogene, RBM4 has the potential to become a biomarker and therapeutic target for various malignant tumors, offering novel possibilities for precision medicine.

PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway.

Our previous studies have showed that C-C motif chemokine ligand 20 (CCL20) advanced tumor progression and enhanced the chemoresistance of cancer cells by positively regulating breast cancer stem cell (BCSC) self-renewal. However, it is unclear whether CCL20 affects breast cancer progression by remodeling the tumor microenvironment (TME). Here, we observed that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were remarkably enriched in TME of CCL20-overexpressing cancer cell orthotopic allograft tumors. Mechanistically, CCL20 activated the differentiation of granulocyte-monocyte progenitors (GMPs) via its receptor C-C motif chemokine receptor 6 (CCR6) leading to the PMN-MDSC expansion. PMN-MDSCs from CCL20-overexpressing cell orthotopic allograft tumors (CCL20-modulated PMN-MDSCs) secreted amounts of C-X-C motif chemokine ligand 2 (CXCL2) and increased ALDH+ BCSCs via activating CXCR2/NOTCH1/HEY1 signaling pathway. Furthermore, C-X-C motif chemokine receptor 2 (CXCR2) antagonist SB225002 enhanced the docetaxel (DTX) effects on tumor growth by decreasing BCSCs in CCL20high-expressing tumors. These findings elucidated how CCL20 modulated the TME to promote cancer development, indicating a new therapeutic strategy by interfering with the interaction between PMN-MDSCs and BCSCs in breast cancer, especially in CCL20high-expressing breast cancer.

Knockdown of Oligosaccharyltransferase Subunit Ribophorin 1 Induces Endoplasmic-Reticulum-Stress-Dependent Cell Apoptosis in Breast Cancer.

Ribophorin 1 (RPN1) is a major part of Oligosaccharyltransferase (OST) complex, which is vital for the N-linked glycosylation. Though it has been verified that the abnormal glycosylation is closely related to the development of breast cancer, the detail role of RPN1 in breast cancer remains unknown. In this study, we explored the public databases to investigate the relationship between the expression levels of OST subunits and the prognosis of breast cancer. Then, we focused on the function of RPN1 in breast cancer and its potential mechanisms. Our study showed that the expression of several OST subunits including RPN1, RPN2, STT3A STT3B, and DDOST were upregulated in breast cancer samples. The protein expression level of RPN1 was also upregulated in breast cancer. Higher expression of RPN1 was correlated with worse clinical features and poorer prognosis. Furthermore, knockdown of RPN1 suppressed the proliferation and invasion of breast cancer cells in vitro and induced cell apoptosis triggered by endoplasmic reticulum stress. Our results identified the oncogenic function of RPN1 in breast cancer, implying that RPN1 might be a potential biomarker and therapeutic target for breast cancer.

TEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer.

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.

AMPK phosphorylates PPARδ to mediate its stabilization, inhibit glucose and glutamine uptake and colon tumor growth.

Peroxisome proliferator-activated receptor δ (PPARδ) is a nuclear receptor transcription factor that plays an important role in the regulation of metabolism, inflammation, and cancer. In addition, the nutrient-sensing kinase 5'AMP-activated protein kinase (AMPK) is a critical regulator of cellular energy in coordination with PPARδ. However, the molecular mechanism of the AMPK/PPARδ pathway on cancer progression is still unclear. Here, we found that activated AMPK induced PPARδ-S50 phosphorylation in cancer cells, whereas the PPARδ/S50A (nonphosphorylation mimic) mutant reversed this event. Further analysis showed that the PPARδ/S50E (phosphorylation mimic) but not the PPARδ/S50A mutant increased PPARδ protein stability, which led to reduced p62/SQSTM1-mediated degradation of misfolded PPARδ. Furthermore, PPARδ-S50 phosphorylation decreased PPARδ transcription activity and alleviated PPARδ-mediated uptake of glucose and glutamine in cancer cells. Soft agar and xenograft tumor model analysis showed that the PPARδ/S50E mutant but not the PPARδ/S50A mutant inhibited colon cancer cell proliferation and tumor growth, which was associated with inhibition of Glut1 and SLC1A5 transporter protein expression. These findings reveal a new mechanism of AMPK-induced PPARδ-S50 phosphorylation, accumulation of misfolded PPARδ protein, and inhibition of PPARδ transcription activity contributing to the suppression of colon tumor formation.

Metformin inhibits PPARδ agonist-mediated tumor growth by reducing Glut1 and SLC1A5 expressions of cancer cells.

As a nuclear receptor, ligand binding and activated PPARδ (peroxisome-proliferator-activated receptor δ) plays an important role in regulation of inflammation, metabolism and cancer, while it is unclear the effect of metformin on PPARδ-mediated cancer cell metabolism. Here we found that PPARδ agonist GW501516 significantly increased Glut1 (Glucose transporter 1) and SLC1A5 (solutecarrier family 1 member 5) gene and protein expressions in HCT-116, SW480, HeLa, and MCF-7 cancer cell lines, while metformin inhibited this event, which was associated with metformin-mediated inhibition of PPARδ activity in response to GW501516. Importantly, GW501516 inhibited the binding of PPARδ to AMPK, while metformin reversed this process. Metformin inhibited Glut1 and SLC1A5 expressions leading to reduced influx of glucose and glutamine in cancer cells, which is associated with reduced tumor growth. These findings suggest that metformin inhibited PPARδ agonist GW501516-induced cancer cell metabolism and tumor growth.

ABCB1 Polymorphisms and Childhood Acute Lymphoblastic Leukemia Risk: A Meta-Analysis.

The association between ATP-binding cassette subfamily B member 1 (ABCB1) C3435T and C1236T polymorphisms and the risk for childhood acute lymphoblastic leukemia (ALL) is inconclusive. We conducted a meta-analysis of all published studies to determine the association of ABCB1 C3435T and C1236T polymorphisms and pediatric ALL risk. A systematic retrieval of relevant publications from the PubMed and Web of Science databases was performed. Data were calculated and statistical analysis was performed using STATA version 12.0 software. Metaanalysis results showed no significant association between C3435T polymorphism and pediatric ALL risk (TT vs. CC: odds ratio [OR] = 1.20, 95% confidence interval [CI] = 0.95-1.52; CT vs. CC: OR = 1.00, 95% CI = 0.82-1.23; the dominant model: OR = 1.07, 95% CI = 0.89-1.29; the recessive model: OR = 1.17, 95% CI = 0.84-1.62). Similarly, there was no association found for the C1236T polymorphism (TT vs. CC: OR = 1.18, 95% CI= 0.82-1.70; CT vs. CC: OR = 1.08, 95% CI = 0.80-1.45; the dominant model: OR = 1.10, 95% CI= 0.83-1.46; the recessive model: OR = 0.98, 95% CI = 0.61-1.58). Similar results were observed in the subgroup analyses on ethnicity and Hardy-Weinberg equilibrium. The present meta-analysis found no evidence for ABCB1 C3435T and C1236T polymorphisms as risk factors for pediatric ALL.