查看更多>>摘要：Lung cancer is the most common cancer and the leading cause of cancer deaths worldwide. In addition to coding genes, the contribution of long noncoding RNA (lncRNA) to non-small cell lung cancer (NSCLC) remains unclear. Here, we explored lncRNA expression profiles by Affymetrix Gene Chip Human Transcriptome Array 2.0 in 37 paired samples of tumorous NSCLC tissues and adjacent nontumorous tissues. We showed that LHFPL3-AS2 is a novel lncRNA, significantly decreased in NSCLC tissues. LHFPL3-AS2 was further validated in an additional 93 paired samples of NSCLC. Low levels of LHFPL3-AS2 expression were highly correlated with poor overall survival, TNM stage, and metastasis of NSCLC patients. Enhanced expression of LHFPL3-AS2 inhibited NSCLC invasion and metastasis in vitro and in vivo. Moreover, downregulation of LHFPL3-AS2 reduced its specific interaction with SFPQ, resulting in more SFPQ binding to the promoter of TXNIP and causing the transcriptional repression of TXNIP, thus finally promoting the migration and invasion of NSCLC cells. Furthermore, LHFPL3AS2 was shown to be regulated by EGR1 under hypoxia.
查看更多>>摘要：MicroRNAs (miRNAs) regulate gene expression to participate in carcinogenesis and tumor progression. Therefore, identification of a malignant phenotype associated with miRNAs and therapeutic targets will contribute substantially in improving nasopharyngeal carcinoma (NPC) treatment. In this study, we demonstrated that overexpression of let-7i-5p promotes the malignant phenotype by acting as an autophagy suppressor by targeting ATG10 and ATG16L1 in NPC. Expression levels of let-7i-5p were markedly increased in NPC and head and neck cancers based on an analysis of the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Using a cohort comprising 150 NPC tissues, we found that let-7i-5p was correlated with advanced stage, recurrence, metastasis, lymph node metastasis, and poor clinical outcomes. In addition to a series of in vitro cellular analyses, in vivo mouse tumor models revealed that let-7i-5p inhibits autophagy and promotes the malignant phenotype of NPC by targeting ATG10 and ATG16L1. Our findings demonstrate that let-7i-5p may represent a promising therapeutic target for NPC treatment.
查看更多>>摘要：In vivo tumor growth is characterized by a necrotic core generated by oxygen and nutrients gradients, which is replicated by in vitro three-dimensional (3D) tumor spheroids but not traditional two-dimensional cell monolayers. Gap junctions provide direct communication between adjacent cells and play a critical role in cancer development, but their effects are still debatable. In this study, we found that connexin 43 (Cx43) reduced the area of necrotic core in colon cancer 3D spheroids, thus providing a growth advantage. This impact is dependent on gap junction channel functions, as the channel blocker carbenoxolone or connexin channel death mutant reverses this effect. Additionally, enhanced glucose uptake was detected in Cx43-overexpressing spheroids, along with upregulated mTOR, downregulated AMPK signaling, increased ATP content, and enhanced oxygen consumption rate. Furthermore, the xenograft mouse model confirmed the growth advantage of Cx43 in vivo. RNAseq data and clinical information from The Cancer Genome Atlas (TCGA) database indicated a more heterogeneous expression pattern of Cx43 in colon cancer compared to normal colon tissue, and higher Cx43 level is associated with worse clinical outcomes. Our data suggest a novel function of connexin in tumor growth, that gap junctions may provide nutrients transmitting routes in lieu of vasculature to meet the increasing metabolic requirement of solid tumors.
查看更多>>摘要：The response to immune checkpoint inhibitors (ICIs) monotherapy remains unsatisfactory in patients with NSCLC. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Here, we identified that HIF-1 alpha inhibition was capable of promoting anti-tumor immunity in NSCLC. We applied NSCLC cell lines and mouse models to evaluate the synergy of combined HIF-1 alpha inhibition and PD-1 blockade on tumor growth and the function of tumor infiltrating lymphocytes (TILs). Public datasets were utilized to investigate patients' prognosis based on expressions of HIF-1 alpha and LOXL2 as well as EMT associated markers and CD8(+) TILs. Moreover, we explored the correlation between HIF-1 alpha and LOXL2 levels and CD8(+) TILs in tumor samples from patients with NSCLC by immunohistochemistry, as well as their association to patients' survival. In vitro, PX-478, an HIF-1 alpha inhibitor, promoted tumor cell apoptosis induced by T cells when combined with ICIs. Furthermore, mice treated with PX-478 and anti-PD-1 antibodies exhibited a marked delay in tumor growth and prolonged survival, which correlated with increased TILs and granzyme B secretion. Besides, patients with high HIF-1 alpha expression exhibited high levels of EMT-related markers and low TILs, indicating an immunosuppressive phenotype. Mechanistically, we observed that HIF-1 alpha inhibition suppressed the EMT phenotypes induced by hypoxia and further alleviated tumor immunosuppression, which was related to blockage of HIF-1 alpha/LOXL2 signaling pathway. In summary, we identified that HIF-1 alpha inhibition could synergize with anti-PD-1 to impair tumor growth in vitro and in vivo. Our data suggest that HIF-1 alpha inhibitors represent a promising treatment to enhance anti-tumor immunity and provide preclinical rationale to evaluate the combination of ICIs with HIF-1 alpha inhibition clinically in NSCLC.
查看更多>>摘要：Clinically, the metastasis of tumor cells is the key factor of death in patients with cancer. In this study, we used a model of metastatic nasopharyngeal carcinoma (NPC) to explore the effects of a new chemical, cinobufagin (CB), combined with cisplatin (DDP). We observed that chemically synthesized CB strongly decreased the metastasis of NPC. Furthermore, a better therapeutic effect was shown when CB was combined with DDP. Molecular analysis revealed that CB induced ENKUR expression by deregulating the PI3K/AKT pathway and suppressing c-Jun, an oncogenic transcriptional factor that binds to the ENKUR promoter and negatively modulated its expression in NPC. ENKUR as a tumor suppressor binds to MYH9 and decreases its expression by recruiting beta-catenin via its enkurin domain to prevent its nuclear accumulation, which therefore suppresses c-Jun-induced MYH9 expression. Subsequently, downregulated MYH9 reduces the enlistment of E3 ligase UBE3A and thus decreases the UBE3A-mediated ubiquitination degradation of p53, a key tumor suppressor that decreases epithelialmesenchymal transition (EMT). Clinical sample analysis demonstrated that the ENKUR expression level was significantly reduced in NPC tissues. Its decreased expression substantially promoted clinical progression and reflected poor prognosis for patients with NPC. This study demonstrated that CB induced ENKUR to repress the beta-catenin/c-Jun/MYH9 signal and thus decreased UBE3A-mediated p53 ubiquitination degradation. As a result, the EMT signal was inactivated to suppress NPC metastasis.
查看更多>>摘要：The largest US cancer health disparity exists in prostate cancer, with Black men having more than a two-fold increased risk of dying from prostate cancer compared to all other races. This disparity is a result of a complex network of factors including socioeconomic status (SES), environmental exposures, and genetics/biology. Inequity in the US healthcare system has emerged as a major driver of disparity in prostate cancer outcomes and has raised concerns that the actual incidence rates may be higher than current estimates. However, emerging studies argue that equalizing healthcare access will not fully eliminate racial health disparities and highlight the important role of biology. Significant differences have been observed in prostate cancer biology between ancestral groups that may contribute to prostate cancer health disparities. Notably, relative to White men, Black men with prostate cancer exhibit increased androgen receptor signaling, genomic instability, metabolic dysregulation, and inflammatory and cytokine signaling. Immediate actions are needed to increase multi-center, interdisciplinary research to bridge the gap between social and biological determinants of prostate cancer health disparities.
查看更多>>摘要：Lung adenocarcinoma is the most common form of lung cancer, accounting for 60% of non-small cell lung cancer (NSCLC) cases in Asian patients. Importantly, nearly half of these patients have epithelial growth factor receptor (EGFR) mutations. Though EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line therapy for NSCLC patients, the development of resistance reduces their efficiency and limits their application. As the complicated and heterogeneous mechanism of acquired resistance among individuals, the efficiency of anti-angiogenesis therapy, immune checkpoint inhibitors, or chemo-radiotherapies is rather less promising. In this research, we investigated the role of the tumor stem cell marker DCLK1 in EGFR-TKI resistance of lung adenocarcinoma. We discovered that DCLK1 was critical in maintaining the stemness of tumor cells through the Wnt/beta-Catenin pathway, which was conducive to the development of EGFR-TKI resistance. Inhibiting DCLK1 activity restored the sensitivity of TKI-resistant tumor cells and organoids. Moreover, our study showed that DCLK1 inhibitor had a synergistic effect in controlling tumor growth when combined with EGFR-TKIs. Overall, our study provides new insights into EGFR-TKI resistant lung adenocarcinoma through inhibition of DCLK1 expression.
Marion, Tony N. N.Carson, James A. A.Thomas, Paul G. G.Makowski, Liza...
11页
查看更多>>摘要：Myeloid-derived suppressor cells (MDSCs) are an immature innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to CD8(+) T cells, a process that requires a specific subtype of dendritic cells (DCs) called con-ventional DC1 (cDC1) which are often dysfunctional in cancer. One way to activate cDC1 is ligation of CD40 which is abundantly expressed by myeloid cells and its agonism leads to myeloid cell activation. Thus, targeting MDSCs while simultaneously expanding cross-presenting DCs represents a promising strategy that, when com-bined with agonistic CD40, may result in long-lasting protective immunity. In this study, we investigated the effect of PKC agonists PEP005 and prostratin on MDSC expansion, differentiation, and recruitment to the tumor microenvironment. Our findings demonstrate that PKC agonists decreased MDSC expansion from hematopoietic progenitors and induced M-MDSC differentiation to an APC-like phenotype that expresses cDC1-related markers via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Simultaneously, PKC agonists favored cDC1 expansion at the expense of cDC2 and plasmacytoid DCs (pDC). Functionally, PKC agonists blunted MDSC suppressive activity and enhanced MDSC cross-priming capacity both in vitro and in vivo. Finally, com-bination of PKC agonism with agonistic CD40 mAb resulted in a marked reduction in tumor growth with a significant increase in intratumoral activated CD8(+) T cells and tissue-resident memory CD8(+) T cells in a syn-geneic breast cancer mouse model. In sum, this work proposes a novel promising strategy to simultaneously target MDSCs and promote APC function that may have highly impactful clinical relevance in cancer patients.
查看更多>>摘要：The abnormal expression or mutation of the plant homeodomain finger protein 14 (PHF14), a recently discovered PHD finger protein, has been reported to link to a wide range of disorders, like the aetiology and pathophysiology of multiple malignancies. Its detailed biological functions, however, still remain unclear. Herein, we discovered that PHF14 expression is strongly associated with the gastrointestinal tumor grade and gastrointestinal disorders, especially colorectal cancer (CRC), with high PHF14 expressions indicating a poor prognosis. Additionally, the mutation rate of PHF14 in CRC patients accounts for a striking proportion of 18%. PHF14 is also implicated in the expression of several oncogenes. In vitro, PHF14 was significantly expressed in patient tissues and in various CRC cell lines, and its expression was closely associated with cell proliferation and growth. Knockdown of PHF14 mediated severe DNA damage and activation of the ATR-CHK1-H2A.X pathway, leading to apoptosis. Strikingly, PHF14 interacted with KIF4A and contributes to the formation of BRCA2/Rad51 foci, indicating that PHF14 is a newly discovered factor that may participate in the formation and recruitment of DNA damage response complexes. These impairments, however, could be alleviated by restoring PHF14 expression. Importantly, inhibiting PHF14 expression in CRC cells might reduce carcinogenesis in vivo. In conclusion, PHF14 is necessary for CRC cell proliferation and growth, and therefore, it might be used as a novel biomarker and therapeutic target for the disease.
Rimkus, Tadas K.Arrigo, Austin B.Zhu, DongqinCarpenter, Richard L....
12页
查看更多>>摘要：Whether tumor suppressor candidate 2 (TUSC2) plays an important role in glioblastoma (GBM) progression is largely unknown. Whether TUSC2 undergoes polyubiquitination is unknown. Herein, we report that TUSC2 protein expression is reduced/lost in GBM compared to normal brain due to protein destabilization; TUSC2 mRNA is equally expressed in both tissues. NEDD4 E3 ubiquitin ligase polyubiquitinates TUSC2 at residue K71, and the TUSC2-K71R mutant is resistant to NEDD4-mediated proteasomal degradation. Analysis of GBM spec-imens showed NEDD4 protein is highly expressed in GBM and the level is inversely correlated with TUSC2 protein levels. Furthermore, TUSC2 restoration induces apoptosis and inhibits patient-derived glioma stem cells (PD-GSCs) in vitro and in vivo. Conversely, TUSC2-knockout promotes PD-GSCs in vitro and in vivo. RNA-Seq analysis and subsequent validations showed GBM cells with TUSC2-knockout expressed increased Bcl-xL and were more resistant to apoptosis induced by a Bcl-xL-specific BH3 mimetic. A TUSC2-knockout gene signature created from the RNA-seq data predicts poor patient survival. Together, these findings establish that NEDD4-mediated polyubiquitination is a novel mechanism for TUSC2 degradation in GBM and that TUSC2 loss pro-motes GBM progression in part through Bcl-xL upregulation.
NSTL
Elsevier