Fusobacterium and Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide and its pathogenesis has been extensively explored over the past decades. Recently, microorganisms in the gastrointestinal tract have emerged as potential etiological agents. In particular, a direct proportional association between Fusobacterium and CRC has been described. Since then, the functional impact of Fusobacterium in CRC development has been studied using various mouse models. Although some epidemiologic studies did not establish an obvious relationship between Fusobacterium and CRC, numerous pathogenic mechanisms leading to the disease have been described. For instance, Fusobacterium can activate the E-cadherin/β-catenin signaling pathway and is associated with particular epigenetic phenotype, such as microsatellite instability (MSI) and hypermethylation, via its strong adhesive and invasive abilities resulting in malignant transformation of epithelial cells. Also, Fusobacterium could alter the tumor microenvironment (TME) significantly by myeloid-derived suppressor cells (MDSCs), tumor associated macrophages (TAMs), and tumor associated neutrophils (TANs) recruitment and local immune suppression. Herein, we provide an in-depth review of the relationship between Fusobacterium and colorectal cancer. In light of the emergence of microbiome-based therapeutics, potential therapies and preventive strategies for colorectal cancer related to Fusobacterium are also discussed

A Robust Nanoparticle Platform for RNA Interference in Macrophages to Suppress Tumor Cell Migration

Macrophages are one of the most abundant immune cells in the solid tumor and their increased density is associated with the specific pathological features of cancers, including invasiveness, metastasis, immunosuppression, neovascularization, and poor response to therapy. Therefore, reprogramming macrophage behavior is emerging as a promising therapeutic modality for cancer treatment. RNA interference (RNAi) technology is one of the powerful strategies for the regulation of macrophage activities by silencing specific genes. However, as polyanionic biomacromolecules, RNAi therapeutics such as small interfering RNA (siRNA) cannot readily cross cell membrane and thus specific delivery vehicles are required to facilitate the cytosolic siRNA delivery. Herein, we developed a robust nanoparticle (NP) platform for efficient siRNA delivery and gene silencing in macrophages. This NP platform is composed of biodegradable poly (ethylene glycol)-b-poly (-caprolactone) (PEG-b-PCL), poly (-caprolactone)-b-poly (2-aminoethyl ethylene phosphate) (PCL-b-PPEEA), and PCL homopolymer. We chose CC-chemokine ligand 18 (CCL-18) as a proof of concept therapeutic target and our results demonstrate that the CCL-18 silencing in macrophages can significantly inhibit the migration of breast cancer cells. The successful regulation of the macrophage behavior demonstrated herein shows great potential as an effective strategy for cancer therapy

Long Noncoding RNA Expression Signatures of Metastatic Nasopharyngeal Carcinoma and Their Prognostic Value

Long noncoding RNAs (lncRNAs) have recently been found to play important roles in various cancer types. The elucidation of genome-wide lncRNA expression patterns in metastatic nasopharyngeal carcinoma (NPC) could reveal novel mechanisms underlying NPC carcinogenesis and progression. In this study, lncRNA expression profiling was performed on metastatic and primary NPC tumors, and the differentially expressed lncRNAs between these samples were identified. A total of 33,045 lncRNA probes were generated for our microarray based on authoritative data sources, including RefSeq, UCSC Knowngenes, Ensembl, and related literature. Using these probes, 8,088 lncRNAs were found to be significantly differentially expressed (2-fold). To identify the prognostic value of these differentially expressed lncRNAs, four lncRNAs (LOC84740, ENST00000498296, AL359062, and ENST00000438550) were selected; their expression levels were measured in an independent panel of 106 primary NPC samples via QPCR. Among these lncRNAs, ENST00000438550 expression was demonstrated to be significantly correlated with NPC disease progression. A survival analysis showed that a high expression level of ENST00000438550 was an independent indicator of disease progression in NPC patients (). In summary, this study may provide novel diagnostic and prognostic biomarkers for NPC, as well as a novel understanding of the mechanism underlying NPC metastasis and potential targets for future treatment

Identification of DHX36 as a tumour suppressor through modulating the activities of the stress-associated proteins and cyclin-dependent kinases in breast cancer

The nucleic acid guanine-quadruplex structures (G4s) are involved in many aspects of cancer progression. The DEAH-box polypeptide 36 (DHX36) has been identified as a dominant nucleic acid helicase which targets and disrupts DNA and RNA G4s in an ATP-dependent manner. However, the actual role of DHX36 in breast cancer remains unknown. In this study, we observed that the gene expression of DHX36 was positively associated with patient survival in breast cancer. The abundance of DHX36 is also linked with pathologic conditions and the stage of breast cancer. By using the xenograft mouse model, we demonstrated that the stable knockdown of DHX36 via lentivirus in breast cancer cells significantly promoted tumour growth. We also found that, after the DHX36 knockdown (KD), the invasion of triple-negative breast cancer cells was enhanced. In addition, we found a significant increase in the number of cells in the S-phase and a reduction of apoptosis with the response to cisplatin. DHX36 KD also desensitized the cytotoxic cellular response to paclitaxel and cisplatin. Transcriptomic profiling analysis by RNA sequencing indicated that DHX36 altered gene expression profile through the upstream activation of TNF, IFNγ, NFκb and TGFβ1. High throughput signalling analysis showed that one cluster of stress-associated kinase proteins including p53, ROCK1 and JNK were suppressed, while the mitotic checkpoint protein-serine kinases CDK1 and CDK2 were activated, as a consequence of the DHX36 knockdown. Our study reveals that DHX36 functions as a tumour suppressor and may be considered as a potential therapeutic target in breast cancer

Identification of DHX36 as a tumour suppressor through modulating the activities of the stress-associated proteins and cyclin-dependent kinases in breast cancer

The nucleic acid guanine-quadruplex structures (G4s) are involved in many aspects of cancer progression. The DEAH-box polypeptide 36 (DHX36) has been identified as a dominant nucleic acid helicase which targets and disrupts DNA and RNA G4s in an ATP-dependent manner. However, the actual role of DHX36 in breast cancer remains unknown. In this study, we observed that the gene expression of DHX36 was positively associated with patient survival in breast cancer. The abundance of DHX36 is also linked with pathologic conditions and the stage of breast cancer. By using the xenograft mouse model, we demonstrated that the stable knockdown of DHX36 via lentivirus in breast cancer cells significantly promoted tumour growth. We also found that, after the DHX36 knockdown (KD), the invasion of triple-negative breast cancer cells was enhanced. In addition, we found a significant increase in the number of cells in the S-phase and a reduction of apoptosis with the response to cisplatin. DHX36 KD also desensitized the cytotoxic cellular response to paclitaxel and cisplatin. Transcriptomic profiling analysis by RNA sequencing indicated that DHX36 altered gene expression profile through the upstream activation of TNF, IFNγ, NFκb and TGFβ1. High throughput signalling analysis showed that one cluster of stress-associated kinase proteins including p53, ROCK1 and JNK were suppressed, while the mitotic checkpoint protein-serine kinases CDK1 and CDK2 were activated, as a consequence of the DHX36 knockdown. Our study reveals that DHX36 functions as a tumour suppressor and may be considered as a potential therapeutic target in breast cancer

Assessing real-world safety concerns of Sacituzumab govitecan: a disproportionality analysis using spontaneous reports in the FDA adverse event reporting system

AimThe aim of this study was to identify potential safety concerns associated with Sacituzumab Govitecan (SG), an antibody-drug conjugate targeting trophoblastic cell-surface antigen-2, by analyzing real-world safety data from the largest publicly available worldwide pharmacovigilance database.MethodsAll data obtained from the FDA Adverse Event Reporting System (FAERS) database from the second quarter of 2020 to the fourth quarter of 2022 underwent disproportionality analysis and Bayesian analysis to detect and assess the adverse event signals of SG, considering statistical significance when the lower limit of the 95% CI >1, based on at least 3 reports.ResultsTotal of 1072 cases were included. The main safety signals were blood and lymphatic system disorders [ROR(95CI)=7.23 (6.43-8.14)], gastrointestinal disorders [ROR(95CI)=2.01 (1.81-2.22)], and relative infection adverse events, such as neutropenic sepsis [ROR(95CI)=46.02 (27.15-77.99)] and neutropenic colitis [ROR(95CI)=188.02 (120.09-294.37)]. We also noted unexpected serious safety signals, including large intestine perforation [ROR(95CI)=10.77 (3.47-33.45)] and hepatic failure [ROR(95CI)=3.87 (1.45-10.31)], as well as a high signal for pneumonitis [ROR(95CI)=9.93 (5.75-17.12)]. Additionally, age sub-group analysis revealed that geriatric patients (>65 years old) were at an increased risk of neutropenic colitis [ROR(95CI)=282.05 (116.36-683.66)], neutropenic sepsis [ROR(95CI)=101.11 (41.83-244.43)], acute kidney injury [ROR(95CI)=3.29 (1.36-7.94)], and atrial fibrillation [ROR(95CI)=6.91 (2.86-16.69)].ConclusionThis study provides crucial real-world safety data on SG, complementing existing clinical trial information. Practitioners should identify contributing factors, employ monitoring and intervention strategies, and focus on adverse events like neutropenic sepsis, large intestine perforation, and hepatic failure. Further prospective studies are needed to address these safety concerns for a comprehensive understanding and effective management of associated risks

Markers of Tumor-Initiating Cells Predict Chemoresistance in Breast Cancer

PURPOSE: Evidence is lacking whether the number of breast tumor-initiating cells (BT-ICs) directly correlates with the sensitivity of breast tumors to chemotherapy. Here, we evaluated the association between proportion of BT-ICs and chemoresistance of the tumors. METHODS: Immunohistochemical staining(IHC) was used to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and proliferating cell nuclear antigen, and TUNEL was used to detect the apoptosis index. The significance of various variables in patient survival was analyzed using a Cox proportional hazards model. The percentage of BT-ICs in breast cancer cell lines and primary breast tumors was determined by ALDH1 enzymatic assay, CD44(+)/CD24(-) phenotype and mammosphere formation assay. RESULTS: ALDH1 expression determined by IHC in primary breast cancers was associated with poor clinical response to neoadjuvant chemotherapy and reduced survival in breast cancer patients. Breast tumors that contained higher proportion of BT-ICs with CD44(+)/CD24(-) phenotype, ALDH1 enzymatic activity and sphere forming capacity were more resistant to neoadjuvant chemotherapy. Chemoresistant cell lines AdrR/MCF-7 and SK-3rd, had increased number of cells with sphere forming capacity, CD44(+)/CD24(-) phenotype and side-population. Regardless the proportion of T-ICs, FACS-sorted CD44(+)/CD24(-) cells that derived from primary tumors or breast cancer lines were about 10-60 fold more resistant to chemotherapy relative to the non- CD44(+)/CD24(-) cells and their parental cells. Furthermore, our data demonstrated that MDR1 (multidrug resistance 1) and ABCG2 (ATP-binding cassette sub-family G member 2) were upregulated in CD44(+)/CD24(-) cells. Treatment with lapatinib or salinomycin reduced the proportion of BT-ICs by nearly 50 fold, and thus enhanced the sensitivity of breast cancer cells to chemotherapy by around 30 fold. CONCLUSIONS: These data suggest that the proportion of BT-ICs is associated with chemotherapeutic resistance of breast cancer. It highlights the importance of targeting T-ICs, rather than eliminating the bulk of rapidly dividing and terminally differentiated cells, in novel anti-cancer strategies

HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading

Association of PIK3CA mutation with outcomes in HER2-positive breast cancer treated with anti-HER2 therapy: A meta-analysis and bioinformatic analysis of TCGA‑BRCA data

Background: This study aimed to comprehensively explore the clinical significance of PIK3CA mutation in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with anti-HER2 therapy. Methods: We systematically searched PubMed, Embase, and the Cochrane databases for eligible studies assessing the association between PIK3CA mutation and outcomes in patients with HER2-positive breast cancer receiving anti-HER2 therapy. The main outcomes included: (1) pathological complete response (pCR) or disease-free survival (DFS) for the neoadjuvant setting; (2) DFS or invasive DFS for the adjuvant setting; (3) objective response rate (ORR), progression-free survival (PFS), time-to-progression (TTP), or overall survival (OS) for the metastatic setting. The mutational landscape of HER2-positive breast cancer according to PIK3CA mutation status was examined based on TCGA breast cancer dataset. Results: Totally, 43 eligible studies, covering 11,099 patients with available data on PIK3CA mutation status, were identified. In the neoadjuvant setting, PIK3CA mutation was significantly associated with a lower pCR rate (OR=0.23, 95% CI 0.19–0.27, p<0.001). This association remained significant irrespective of the type of anti-HER2 therapy (single-agent or dual-agent) and hormone receptor status. There were no significant differences in DFS between PIK3CA mutated and wild-type patients in either the neoadjuvant or adjuvant settings. In the metastatic setting, PIK3CA mutation predicted worse ORR (OR=0.26, 95%CI 0.17–0.40, p<0.001), PFS (HR=1.28, 95%CI 1.03–1.59, p = 0.024) and TTP (HR=2.27, 95%CI 1.54–3.34, p<0.001). However, no significant association was observed between PIK3CA mutation status and OS. Distinct mutational landscapes were observed in HER2-positive breast cancer between individuals with PIK3CA mutations and those with wild-type PIK3CA. Conclusions: PIK3CA mutation was significantly associated with a lower pCR rate in HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy. In the metastatic setting, PIK3CA mutation was predictive of worse ORR, PFS and TTP. These results suggest the potential for developing PI3K inhibitors as a therapeutic option for these patients

RYBP Inhibits Progression and Metastasis of Lung Cancer by Suppressing EGFR Signaling and Epithelial-Mesenchymal Transition

Lung cancer (LC) is a common lethal malignancy with rapid progression and metastasis, and Ring1 and YY1 binding protein (RYBP) has been shown to suppress cell growth in human cancers. This study aimed to investigate the role of RYBP in LC progression and metastasis. In this study, a total of 149 LC patients were recruited, and the clinical stage of their tumors, metastasis status, survival time, presence of epidermal growth factor receptor (EGFR) mutation, and RYBP expression levels were measured. RYBP silencing and overexpression were experimentally performed in LC cell lines and in nude mice, and the expressions of genes in EGFR-related signaling pathways and epithelial-mesenchymal transition (EMT) were detected. The results showed that RYBP was downregulated in LC compared with adjacent normal tissues, and low RYBP expression was associated with a more severe clinical stage, high mortality, high metastasis risk, and poor survival. Cell proliferation and xenograft growth were inhibited by RYBP overexpression, whereas proliferation and xenograft growth were accelerated by RYBP silencing. EGFR and phosphorylated-EGFR levels were upregulated when RYBP was silenced, whereas EGFR, p-EGFR, p-AKT, and p-ERK were downregulated when RYBP was overexpressed. Low RYBP expression was related to a high metastasis risk, and metastasized tumors showed low RYBP levels. Cell migration and invasion were promoted by silencing RYBP but were inhibited by overexpressed RYBP. In addition, the EMT marker vimentin showed diminished expression, and E-cadherin was promoted by the overexpression of RYBP. In conclusion, our data suggest that RYBP suppresses cell proliferation and LC progression by impeding the EGFR-ERK and EGFR-AKT signaling pathways and thereby inhibiting cell migration and invasion and LC metastasis through the suppression of EMT