Targeting SHCBP1 Inhibits Tumor Progression by Restoring Ciliogenesis in Ductal Carcinoma.

Primary cilia detect and transmit environmental signals into cells. Primary cilia are absent in a subset of ductal carcinomas characterized by distinctive biological activities, and recovery of cilia with normal functionality has been shown to have therapeutic potential in some cancer types. Therefore, elucidation of the underlying mechanism and clinical significance of ciliary loss in ductal carcinomas could help develop effective treatment strategies. Here, we identified a link between SHCBP1 and cilia in ductal carcinomas. Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Single-cell transcriptome analysis revealed a functional connection between SHCBP1 deficiency and increased tumor ciliogenesis. SHCBP1 ablation restored ciliogenesis in unciliated ductal carcinoma by promoting the proximity between the midbody remnant (MBR) and centrosome through enhanced Rab8 GTPase activity and Rab8GTP positioning within the MBR. Inhibition of tumor progression by SHCBP1 loss relied on the recovery of ciliogenesis. Analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis. Restoring ciliogenesis via SHCBP1 ablation elicited therapeutic effects in patient-derived xenograft models. Together, this study delineates that induction of MBR-centrosome proximity through SHCBP1-deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas.

Targeting NUF2 suppresses gastric cancer progression through G2/M phase arrest and apoptosis induction.

BACKGROUND: Gastric cancer (GC), a malignant tumor with poor prognosis, is one of the leading causes of cancer-related deaths worldwide; consequently, identifying novel therapeutic targets is crucial for its corresponding treatment. NUF2, a component of the NDC80 kinetochore complex, promotes cancer progression in multiple malignancies. Therefore, this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression. METHODS: Clinical samples from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021, cell count assays, colony formation assays, and cell-derived xenotransplantation (CDX) models were used to determine the effects of NUF2 on GC progression. Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis. A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression. Transcriptomics was used to investigate the NUF2-associated molecular mechanisms. Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors. Finally, CDX, organoid, and patient-derived xenograft (PDX) models were used to examine the efficacy of the NUF2 inhibitor in GC. RESULTS: NUF2 expression was significantly increased in GC and was negatively correlated with prognosis. The deletion of NUF2 suppressed GC progression both in vivo and in vitro. NUF2 significantly regulated the mitogen-activated protein kinase (MAPK) pathway, promoted G2/M phase transition, and inhibited apoptosis in GC cells. Additionally, quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells, organoids, CDX, and PDX models. CONCLUSIONS: Collectively, NUF2-mediated G2/M phase transition and apoptosis inhibition promoted GC progression; additionally, NUF2 inhibitors exhibited potent anti-GC activity. This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.

Self-assembled metal-polyphenolic based multifunctional nanomedicine to improve therapy treatment of pancreatic cancer by inhibition of glutamine metabolism.

Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.

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Recent studies have shown that the formation of the primary cilium is associated with a specific cellular organelle known as the midbody remnant (MBR), which is a point-like organelle formed by shedding of the midbody at the end of mitosis. MBRs move along the cell surface close to the center body and regulate it to form primary cilia at the top of the centriole. Primary cilia can act as an organelle to inhibit tumorigenesis, and it is lost in a variety of tumors. Studies have shown that the accumulation of MBRs in tumor cells affects ciliogenesis; in addition, both MBRs and primary cilia are degraded in tumor cells through the autophagy pathway, and MBRs can also transfer tumor signaling pathway factors to primary cilia affecting tumorigenesis. In this article, the basic structure and the formation process of MBR and primary cilia are reviewed and the mechanism of MBRs regulating ciliogenesis is elaborated. The significance of MBR-mediated ciliogenesis in tumorigenesis and its potential as a target for cancer treatment are discussed.

SHCBP1 Overexpression Aggravates Pancreatitis by Triggering the Loss of Primary Cilia.

Primary cilia are microtubule-based organelles that mediate various biological processes. Pancreatic cells are typically ciliated; however, the role of primary cilia in acute pancreatitis (AP) is largely unknown. Here, we report that the loss of primary cilia, mediated by SHCBP1 (SHC1 binding protein), exerted a provocative effect on AP. Primary cilia are extensively lost in inflamed pancreatic cells in vitro and in mouse tissues with AP in vivo. Abrogation of primary cilia aggravated lipopolysaccharide (LPS)-induced inflammation in pancreatic cells. Mechanistically, AP induced the overexpression of SHCBP1 mitotic factor, which is localized to the base of primary cilia. SHCBP1 deficiency relieved LPS- and cerulein-induced pancreatitis by preventing the loss of primary cilia in vitro and in vivo. Collectively, we reveal that inflammation-induced loss of primary cilia aggravates AP. Furthermore, abrogating SHCBP1 to prevent primary cilia loss is an efficient strategy to combat AP.

Knockout of Shcbp1 sensitizes immunotherapy by regulating α-SMA positive cancer-associated fibroblasts.

The crucial role of cancer-associated fibroblasts (CAFs) in promoting T-cell exclusion has a significant impact on tumor immune evasion and resistance to immunotherapy. Therefore, enhancing T-cell infiltration into solid tumors has emerged as a pivotal area of research. We achieved a conventional knockout of Shcbp1 (Shcbp1-/- ) through CRISPR/Cas9 gene editing and crossed these mice with spontaneous breast cancer MMTV-PyMT mice, resulting in PyMT Shcbp1-/- mice. The different CAF subtypes were detected by flow cytometry analysis (FCA). We evaluated collagen and CAFs levels using Sirius red staining, immunohistochemistry (IHC), and immunofluorescence (IF). Primary tumor cells and CAFs were isolated from both PyMT Shcbp1+/+ and PyMT Shcbp1-/- mice. We analyzed CAFs' proliferation, invasion, migration, apoptosis, and cell cycle. Transwell coculture experiments were performed with primary tumor cells and CAFs to evaluate the role of CAFs in increasing the sensitivity of tumor cells to Erdafitinib. Tumors from PyMT Shcbp1+/+ and PyMT Shcbp1-/- mice were orthotopically transplanted to assess the therapeutic effect of the Erdafitinib and PD-1 combination. CAFs and T-cell infiltration in these tumors were assessed using FCA and IF. Knockout of Shcbp1 leads to a significant reduction in tumor burden, promotes longer survival, and decreases CAFs in MMTV-PyMT. Moreover, knockout of Shcbp1 enhances the sensitivity of Erdafitinib, leading to effective inhibition of CAFs' proliferation and invasion, as well as the induction of apoptosis. Additionally, it results in cell cycle arrest at the G2/M phase in vitro. Meanwhile, Shcbp1-/- CAFs change the sensitivity of Shcbp1-/- tumor cells to Erdafitinib compared to Shcbp1+/+ CAFs. Importantly, knockout of Shcbp1 boosts the effectiveness of Erdafitinib in combination with immune checkpoint blockade therapy by augmenting T-cell infiltration through CAFs regulation in vivo. Our findings demonstrate that knockout of Shcbp1 holds significant potential in enhancing the therapeutic response of Erdafitinib combined with PD-1 antibody treatment, offering promising prospects for future breast cancer therapies.

Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment.

Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing effective strategies for PC treatment is of utmost importance. Here, we revealed that SHCBP1 is significantly overexpressed in PC and negatively correlated with patient prognosis. Knockout of SHCBP1 inhibits the proliferation and migration of PC cells in vitro, and suppresses the tumor growth in vivo. In addition, we identified AZD5582 as a novel inhibitor of SHCBP1, which efficiently restrains the growth of PC in cell lines, organoids, and patient-derived xenografts. Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies.

Probiotics, prebiotics, and postbiotics in health and disease.

The gut microbiota and its homeostasis play a crucial role in human health. However, for some diseases related to the gut microbiota, current traditional medicines can only relieve symptoms, and it is difficult to solve the root causes or even cause side effects like disturbances in the gut microbiota. Increasing clinical studies and evidences have demonstrated that probiotics, prebiotics, and postbiotics can prevent and treat various diseases, but currently they can only be used as dietary supplements rather than medicines, which restricts the application of probiotics in the field of medicine. Here, this review analyzes the importance of gut microbiota in human health and the current problems of traditional medicines, and systematically summarizes the effectiveness and mechanisms of probiotics, prebiotics, and postbiotics in maintaining health and treating diseases based on animal models and clinical trials. And based on current research outcomes and development trends in this field, the challenges and prospects of their clinical application in maintaining health, alleviating and treating diseases are analyzed. It is hoped to promote the application of probiotics, prebiotics, and postbiotics in disease treatment and open up new frontiers in probiotic research.

Exploring the role of PMEPA1 in gastric cancer.

Although there are several treatments available for gastric cancer (GC), the prognosis of the disease is still poor due to many factors, such as late diagnosis and tumor heterogeneity. To identify potential therapeutic targets, bioinformatics techniques and clinical sample validation were employed and prostate transmembrane protein androgen induced 1 (PMEPA1) was selected for further study. In the present study, we found that elevated PMEPA1 expression correlates with a worse prognosis and weaker anti-tumor immunity in GC patients. Moreover, our study showed that PMEPA1 not only influences cell proliferation, clone formation, invasion, and migration in vitro, but also plays an important role in GC progression in vivo. Mechanically, PMEPA1 exerts its oncogenic effects through activating the Wnt/ß-catenin signaling pathway. Therefore, PMEPA1 is a potential target for treating GC effectively.

PICH Activates Cyclin A1 Transcription to Drive S-Phase Progression and Chemoresistance in Gastric Cancer.

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the backbone of postoperative adjuvant treatment for gastric cancer. However, fewer than half of patients with gastric cancer benefit from 5-FU-based chemotherapies owing to chemoresistance and limited clinical biomarkers. Here, we identified the SNF2 protein Polo-like kinase 1-interacting checkpoint helicase (PICH) as a predictor of 5-FU chemosensitivity and characterized a transcriptional function of PICH distinct from its role in chromosome separation. PICH formed a transcriptional complex with RNA polymerase II (Pol II) and ATF4 at the CCNA1 promoter in an ATPase-dependent manner. Binding of the PICH complex promoted cyclin A1 transcription and accelerated S-phase progression. Overexpressed PICH impaired 5-FU chemosensitivity in human organoids and patient-derived xenografts. Furthermore, elevated PICH expression was negatively correlated with survival in postoperative patients receiving 5-FU chemotherapy. Together, these findings reveal an ATPase-dependent transcriptional function of PICH that promotes cyclin A1 transcription to drive 5-FU chemoresistance, providing a potential predictive biomarker of 5-FU chemosensitivity for postoperative patients with gastric cancer and prompting further investigation into the transcriptional activity of PICH. SIGNIFICANCE: PICH binds Pol II and ATF4 in an ATPase-dependent manner to form a transcriptional complex that promotes cyclin A1 expression, accelerates S-phase progression, and impairs 5-FU chemosensitivity in gastric cancer.

Exploring the role of FBXO5 in gastric cancer.

Gastric cancer is one of the most common lethal malignancies in the world, especially in China. Due to the ineffective screening of early gastric cancer and drug resistance of the advanced, the prognosis of gastric cancer remains dismal. Based on bioinformatics and tissue microarray analyses, FBXO5 was selected for analysis in this study. Here, we report the function of FBXO5 in gastric cancer, showing for the first time that it contributes to tumor cell proliferation, clone formation, invasion and migration. In these preliminary findings, FBXO5 promoted the transition of the cell cycle from the G0/G1 to the G2/M phase, which likely resulted from FBXO5 interacting with CDK1 and NCAPG proteins. The relevant mechanism needs to be explored. In addition, FBXO5 participated in the tumor microenvironment and was negatively related to immune activation. FBXO5, an oncogene, plays a role in tumor initiation and progression, and is expected to be a potential target for gastric cancer treatment.

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress.

BACKGROUND & AIMS: Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. METHODS: Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. RESULTS: Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. CONCLUSIONS: Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.

Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer.

BACKGROUND: Novel therapeutic strategies are urgently required to improve clinical outcomes of gastric cancer (GC). KIF15 cooperates with KIF11 to promote bipolar spindle assembly and formation, which is essential for proper sister chromatid segregation. Therefore, we speculated that the combined inhibition of KIF11 and KIF15 might be an effective strategy for GC treatment. Hence, to test this hypothesis, we aimed to evaluate the combined therapeutic effect of KIF15 inhibitor KIF15- IN-1 and KIF11 inhibitor ispinesib in GC. METHODS: We validated the expression of KIF11 and KIF15 in GC tissues using immunohistochemistry and immunoblotting. Next, we determined the effects of KIF11 or KIF15 knockout on the proliferation of GC cell lines. Finally, we investigated the combined effects of the KIF11 and KIF15 inhibitors both in vitro and in vivo. RESULTS: KIF11 and KIF15 were overexpressed in GC tissues than in the adjacent normal tissues. Knockout of either KIF11 or KIF15 inhibited the proliferative and clonogenic abilities of GC cells. We found that the KIF15 knockout significantly increased ispinesib sensitivity in GC cells, while its overexpression showed the opposite effect. Further, using KIF15-IN-1 and ispinesib together had a synergistic effect on the antitumor proliferation of GC both in vitro and in vivo. CONCLUSION: This study shows that the combination therapy of inhibiting KIF11 and KIF15 might be an effective therapeutic strategy against gastric cancer.

Present and Future Prospects of the Anti-cancer Activities of Saikosaponins.

Since their discovery, saikosaponins (SSs) have been found to play an important role in treating a variety of cancers via diverse mechanisms of action. This review summarizes the current research status and prospects of the anti-cancer activities of SSs, providing novel insights into the limitations of current studies. In addition, it discusses whether SSs can be applied in immunotherapy and the possible mechanisms by which SSs may facilitate immunotherapy. The research is significant to understanding the anti-cancer potents of SSs in the development of SSs-based therapeutic strategies and clinical practice.

Therapeutic strategies targeting uPAR potentiate anti-PD-1 efficacy in diffuse-type gastric cancer.

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer (GC) associated with low HER2 positivity rate and insensitivity to chemotherapy and immune checkpoint inhibitors. Here, we identify urokinase-type plasminogen activator receptor (uPAR) as a potential therapeutic target for DGC. We have developed a novel anti-uPAR monoclonal antibody, which targets the domains II and III of uPAR and blocks the binding of urokinase-type plasminogen activator to uPAR. We show that the combination of anti-uPAR and anti-Programmed cell death protein 1 (PD-1) remarkably inhibits tumor growth and prolongs survival via multiple mechanisms, using cell line-derived xenograft and patient-derived xenograft mouse models. Furthermore, uPAR chimeric antigen receptor-expressing T cells based on the novel anti-uPAR effectively kill DGC patient-derived organoids and exhibit impressive survival benefit in the established mouse models, especially when combined with PD-1 blockade therapy. Our study provides a new possibility of DGC treatment by targeting uPAR in a unique manner.

The role of long non-coding RNA FGD5-AS1 in cancer.

Long noncoding RNAs (lncRNAs) refers to a class of RNAs that have at least 200 nucleotides and do not encode proteins, and the relationship between lncRNA and cancer has recently attracted considerable research attention. The lncRNA FGD5-AS1 is a newly discovered lncRNA with a length of 3772 nucleotides. Studies have found that FGD5-AS1 is abnormally highly expressed in many cancer tissues and was closely related to the lymph node metastasis, tumor invasion, survival time, and recurrence rate of various cancers. Mechanistic analyses show that FGD5-AS1 can stabilize mRNA expression by sponging miRNA, which not only induces cancer cell proliferation, metastasis, invasion, and chemoresistance in vitro, but also promotes tumor growth and metastasis in vivo. In addition, FGD5-AS1 can serve as a diagnostic or prognostic marker for a variety of cancers. This review demonstrates the clinical significance of FGD5-AS1 in human cancer and its role in tumorigenesis and tumor progression.

Improving therapeutic resistance: beginning with targeting the tumor microenvironment.

Cancer is a serious threat to human health and life. The tumor microenvironment (TME) not only plays a key role in the occurrence, development and metastasis of cancer, but also has a profound impact on treatment resistance. To improve and solve this problem, an increasing number of strategies targeting the TME have been proposed, and great progress has been made in recent years. This article reviews the characteristics and functions of the main matrix components of the TME and the mechanisms by which each component affects drug resistance. Furthermore, this article elaborates on targeting the TME as a strategy to treat acquired drug resistance, reduce tumor metastasis, recurrence, and improve efficacy.