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The Journal of Clinical Investigation Dec 2023Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal...
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
Topics: Animals; Humans; Mice; Claudin-2; Colitis; Colitis-Associated Neoplasms; Dextran Sulfate; Disease Models, Animal; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice, Inbred C57BL; Survivin
PubMed: 37815870
DOI: 10.1172/JCI170771 -
Cancers Aug 2023Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines.
PubMed: 37686543
DOI: 10.3390/cancers15174265 -
Cell Death Discovery Sep 2023The inhibitor of apoptosis protein survivin has a critical regulatory role in carcinogenesis and treatment tolerance in colorectal cancer (CRC). However, the targeted...
The inhibitor of apoptosis protein survivin has a critical regulatory role in carcinogenesis and treatment tolerance in colorectal cancer (CRC). However, the targeted drugs for survivin protein are extremely limited. In the present research, we discovered that Tanshinone IIA (Tan IIA) played a dual regulatory role in inhibiting tumorigenesis and reversing 5-Fu tolerance via modulating the expression and phosphorylation of survivin in CRC cells. Mechanistically, Tan IIA suppressed the Akt/WEE1/CDK1 signaling pathway, which led to the downregulation of survivin Thr34 phosphorylation and destruction of the interaction between USP1 and survivin to promote survivin ubiquitination and degradation. Furthermore, Tan IIA significantly facilitated chemoresistant CRC cells to 5-Fu sensitivity. These results revealed that Tan IIA possessed a strong antitumor activity against CRC cells and could act as an up-and-coming agent for treating CRC and overcoming chemotherapy resistance.
PubMed: 37749082
DOI: 10.1038/s41420-023-01622-8 -
International Journal of Biological... 2024Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or...
Nasopharyngeal carcinoma (NPC) is the most common cancer originating in the nasopharynx. Despite continuous improvement in treatment strategies, recurrence or persistence of cancer after radiotherapy is still inevitable, highlighting the need to identify therapeutic resistance factors and develop effective methods for NPC treatment. Herein, we found that TRAF4 is overexpressed in NPC cells and tissues. Knockdown TRAF4 significantly increased the radiosensitivity of NPC cells, possibly by inhibiting the Akt/Wee1/CDK1 axis, thereby suppressing survivin phosphorylation and promoting its degradation by FBXL7. TRAF4 is positively correlated with p-Akt and survivin in NPC tissues. High protein levels of TRAF4 were observed in acquired radioresistant NPC cells, and knockdown of TRAF4 overcomes radioresistant and the xenograft mouse model. Altogether, our study highlights the TRAF4-survivin axis as a potential therapeutic target for radiosensitization in NPC.
Topics: Humans; Animals; Mice; Carcinoma; Nasopharyngeal Neoplasms; Proto-Oncogene Proteins c-akt; Survivin; TNF Receptor-Associated Factor 4; Signal Transduction; Nasopharyngeal Carcinoma; Ubiquitination
PubMed: 38164179
DOI: 10.7150/ijbs.87180 -
CNS Neuroscience & Therapeutics Apr 2024Cognitive impairment is associated with reduced hippocampal neurogenesis; however, the causes of decreased hippocampal neurogenesis remain highly controversial. Here, we...
AIMS
Cognitive impairment is associated with reduced hippocampal neurogenesis; however, the causes of decreased hippocampal neurogenesis remain highly controversial. Here, we investigated the role of survivin in the modulation of hippocampal neurogenesis in AD.
METHODS
To investigate the effect of survivin on neurogenesis in neural stem cells (NSCs), we treated mouse embryonic NSCs with a survivin inhibitor (YM155) and adeno-associated viral survivin (AAV-Survivin). To explore the potential role of survivin expression in AD, AAV9-Survivin or AAV9-GFP were injected into the dentate gyrus (DG) of hippocampus of 7-month-old wild-type and 5XFAD mice. Cognitive function was measured by the Y maze and Morris water maze. Neurogenesis was investigated by BrdU staining, immature, and mature neuron markers.
RESULTS
Our results indicate that suppression of survivin expression resulted in decreased neurogenesis. Conversely, overexpression of survivin using AAV-Survivin restored neurogenesis in NSCs that had been suppressed by YM155 treatment. Furthermore, the expression level of survivin decreased in the 9-month-old 5XFAD compared with that in wild-type mice. AAV-Survivin-mediated overexpression of survivin in the DG in 5XFAD mice enhanced neurogenesis and cognitive function.
CONCLUSION
Hippocampal neurogenesis can be enhanced by survivin overexpression, suggesting that survivin could serve as a promising therapeutic target for the treatment of AD.
Topics: Animals; Mice; Alzheimer Disease; Cognition; Disease Models, Animal; Hippocampus; Mice, Transgenic; Neurogenesis; Survivin
PubMed: 37904343
DOI: 10.1111/cns.14509 -
Advanced Biomedical Research 2023Impaired levels of surviving are associate with increased survival of tumor cells. In this study, we intended to profile the microRNAs (miRNAs) targeting survivin in the...
BACKGROUND
Impaired levels of surviving are associate with increased survival of tumor cells. In this study, we intended to profile the microRNAs (miRNAs) targeting survivin in the tumoral and marginal tissues obtained from Iranian patients with colorectal cancer (CRC).
MATERIALS AND METHODS
Fifty CRC patients of Iranian Azari ethnicity were recruited. The RNA content of the tumoral and marginal tissues was isolated and the transcript levels of miR-34a, miR-16, miR-150, and miR-203a and survivin were determined through quantitative Real-time PCR.
RESULTS
The mRNA expression of survivin was significantly increased (fold change = 3.21, = 0.0029) in the tumoral tissues in comparison to the marginal tissues. There was significant downregulation of miR-16 (fold change = 0.28, = 0.003) and miR-203a (fold change = 0.36, = 0.014) in the tumoral samples in comparison to marginal samples. There was an inverse significant correlation (rho = -0.81; < 0.001) between the expression of miR-203a and mRNA expression of survivin in the tumoral tissues of CRC patients. The mRNA expression of survivin was higher significantly in the tumoral tissues of CRC patients with lymph node metastasis in comparison to those without lymph node metastasis ( = 0.020). In addition, there was a significantly higher miR-203 expression level in the tumoral tissues of CRC patients with lymph node metastasis in comparison to those without lymph node metastasis ( = 0.011).
CONCLUSION
It is suggested that miR-203 plays an oncogenic role in CRC cancer by regulating survivin and lymph node metastasis.
PubMed: 38073748
DOI: 10.4103/abr.abr_233_22 -
International Journal of Molecular... Nov 2023Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without... (Review)
Review
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) represents a promising anticancer agent, as it selectively induces apoptosis in transformed cells without altering the cellular machinery of healthy cells. Unfortunately, the presence of TRAIL resistance mechanisms in a variety of cancer types represents a major hurdle, thus limiting the use of TRAIL as a single agent. Accumulating studies have shown that TRAIL-mediated apoptosis can be facilitated in resistant tumors by combined treatment with antitumor agents, ranging from synthetic molecules to natural products. Among the latter, flavonoids, the most prevalent polyphenols in plants, have shown remarkable competence in improving TRAIL-driven apoptosis in resistant cell lines as well as tumor-bearing mice with minimal side effects. Here, we summarize the molecular mechanisms, such as the upregulation of death receptor (DR)4 and DR5 and downregulation of key anti-apoptotic proteins [e.g., cellular FLICE-inhibitory protein (c-FLIP), X-linked inhibitor of apoptosis protein (XIAP), survivin], underlying the TRAIL-sensitizing properties of different classes of flavonoids (e.g., flavones, flavonols, isoflavones, chalcones, prenylflavonoids). Finally, we discuss limitations, mainly related to bioavailability issues, and future perspectives regarding the clinical use of flavonoids as adjuvant agents in TRAIL-based therapies.
Topics: Animals; Mice; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Flavonoids; Ligands; Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha
PubMed: 38068921
DOI: 10.3390/ijms242316596 -
Cancers Apr 2024Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis.... (Review)
Review
Survivin was initially identified as a member of the inhibitor apoptosis (IAP) protein family and has been shown to play a critical role in the regulation of apoptosis. More recent studies showed that survivin is a component of the chromosome passenger complex and acts as an essential mediator of mitotic progression. Other potential functions of survivin, such as mitochondrial function and autophagy, have also been proposed. Survivin has emerged as an attractive target for cancer therapy because its overexpression has been found in most human cancers and is frequently associated with chemotherapy resistance, recurrence, and poor survival rates in cancer patients. In this review, we discuss our current understanding of how survivin mediates various aspects of malignant transformation and drug resistance, as well as the efforts that have been made to develop therapeutics targeting survivin for the treatment of cancer.
PubMed: 38730657
DOI: 10.3390/cancers16091705 -
Frontiers in Immunology 2024Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal....
INTRODUCTION
Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes.
METHODS
Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001.
RESULTS
In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3 and CD8 cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy.
DISCUSSION
We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.
Topics: Humans; Animals; Mice; beta Catenin; Wnt Signaling Pathway; Neoplasm Recurrence, Local; Immunotherapy; Glioma; Tumor Microenvironment
PubMed: 38449858
DOI: 10.3389/fimmu.2024.1342625 -
Asian Pacific Journal of Cancer... Sep 2023This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1),...
BACKGROUND
This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1), and survivin in patients with advanced non-small cell lung cancer (NSCLC) to predict response to chemotherapy.
METHODS
TUBB3, RRM1, APE1, and survivin expression levels were determined using immunohistochemistry. Protein expression was validated in Car/Pac-resistant human H1792 and A549 cells. This study included 86 patients, among whom 34 received cisplatin (Cis)/gemcitabine (Gem) and 52 received carboplatin (Car)/paclitaxel (Pac).
RESULTS
Patients with low TUBB3 expression and high RRM1 and survivin expression had higher response rates than those with low RRM1 and survivin expression and high TUBB3 expression in the Car/Pac regimen. The multivariate analysis indicated that TUBB3 and RRM1 were significant independent predictive biomarkers for the Car/Pac regimen; however, there was no association between any protein and overall response in patients treated with this regimen. In the Cis/Gem regimen, only high TUBB3 expression was associated with poor overall survival; however, it did not exhibit a prognostic ability.
CONCLUSION
The expression levels of TUBB3 and RRM1 in NSCLC cells are potential predictive biomarkers, but not prognostic factors, of response to chemotherapy in patients with NSCLC receiving the Car/Pac regimen.
Topics: Humans; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; DNA-Binding Proteins; Endonucleases; Lung Neoplasms; Paclitaxel; Prognosis; Ribonucleoside Diphosphate Reductase; Survivin; Tubulin; Tumor Suppressor Proteins
PubMed: 37774051
DOI: 10.31557/APJCP.2023.24.9.3003