The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A ...virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA-treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.
Hypoxia occurs naturally at high-altitudes and pathologically in hypoxic solid tumors. Here, we report that genes involved in various human cancers evolved rapidly in Tibetans and six Tibetan ...domestic mammals compared to reciprocal lowlanders. Furthermore, m
A modified mRNA binding protein YTHDF1, one of evolutionary positively selected genes for high-altitude adaptation is amplified in various cancers, including non-small cell lung cancer (NSCLC). We show that YTHDF1 deficiency inhibits NSCLC cell proliferation and xenograft tumor formation through regulating the translational efficiency of CDK2, CDK4, and cyclin D1, and that YTHDF1 depletion restrains de novo lung adenocarcinomas (ADC) progression. However, we observe that YTHDF1 high expression correlates with better clinical outcome, with its depletion rendering cancerous cells resistant to cisplatin (DDP) treatment. Mechanistic studies identified the Keap1-Nrf2-AKR1C1 axis as the downstream mediator of YTHDF1. Together, these findings highlight the critical role of YTHDF1 in both hypoxia adaptation and pathogenesis of NSCLC.
AXL is a member of the TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases family (RTKs), and its abnormal expression has been linked to clinicopathological features and poor prognosis of cancer ...patients. There is mounting evidence supporting AXL's role in the occurrence and progression of cancer, as well as drug resistance and treatment tolerance. Recent studies revealed that reducing AXL expression can weaken cancer cells' drug resistance, indicating that AXL may be a promising target for anti-cancer drug treatment. This review aims to summarize the AXL's structure, the mechanisms regulating and activating it, and its expression pattern, especially in drug-resistant cancers. Additionally, we will discuss the diverse functions of AXL in mediating cancer drug resistance and the potential of AXL inhibitors in cancer treatment.
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, and it is one of the leading causes of cancer death in both men and women worldwide due to diagnosis in the ...advanced stage, rapid metastasis, and recurrence. At present, precision molecular targeted therapeutics directed toward NSCLC driven genes has made great progress and significantly improved the overall survival of patients with NSCLC, but can easily lead to acquired drug resistance. New methods are needed to develop real-time monitoring of drug efficacy and drug resistance, such as new molecular markers for more effective early detection and prediction of prognosis. Exosomes are nano-sized extracellular vesicles, containing proteins, nucleic acids and lipids, which are secreted by various cells, and they play an important role in the development of lung cancer by controlling a wide range of pathways. Tumor-derived exosomes are of great significance for guiding the targeted therapy of NSCLC and exosomes themselves can be a target for treatment. In this review, we describe the potential roles of tumor-derived exosomes and their clinical significance in NSCLC.
As a transcription coactivator, Yes‐associated protein 1 (YAP1)'s role in tumorigenesis is well established. However, the mechanism of YAP1‐regulating long noncoding RNAs (lncRNA) in tumors is still ...largely unknown. Here, a YAP1 target gene, long intergenic noncoding RNA 00152 (LINC00152), which is highly expressed in colorectal cancer (CRC), is identified. The oncogenic functions of LINC00152 in CRC are demonstrated by a panel of in vitro and in vivo experiments. Further studies reveal the potential downstream mechanisms of LINC00152, which can act as a competing endogenous RNA sponging with miR‐632 and miR‐185‐3p to regulate Fascin actin‐bundling protein 1 (FSCN1) expression and thus promote the malignant proliferation and metastasis in CRC cells. Targeting the YAP1/LINC00152/FSCN1 axis inhibits the progression of CRC. This finding provides a new regulatory model of the “YAP1‐lncRNA” in CRC, which gives rise to a new perspective, “YAP1/LINC00152/miR‐632‐miR‐185‐3p/FSCN1,” to explore the cancer‐promoting mechanism of YAP1 involved in CRC.
Cancer‐associated long noncoding RNAs (lncRNAs) are emerging as critical regulators in tumorigenesis. Here, a Yes‐associated protein 1 (YAP1) target lncRNA LINC00152 is identified, and a critical role of YAP1/LINC00152/FSCN1 axis in the tumorigenesis of colorectal cancer (CRC) is revealed, which may provide a potential new target for CRC diagnosis and therapy.
Everolimus is a kind of mammalian target of rapamycin (mTOR) inhibitors. Activated mitogen-activated protein kinase interacting kinases/eukaryotic translation initiation factor 4E (MNK/eIF4E) axis ...plays a crucial role in resistance to Everolimus in non-small cell lung cancer (NSCLC). The eIF4E phosphorylation increased by mTOR inhibitors is mainly mediated by MNKs. However, the mechanisms are poorly understood. Recently, extensive reprogramming of miRNA profiles has also been found after long-term mTOR inhibitor exposure. Our previous studies have confirmed that tumor suppressor miR-7-5p is decreased in A549 cells after treatment with Everolimus. Exactly, MNK1 is the target of miR-7-5p. In this study, we investigated the biological functions and potential molecular mechanisms of miR-7-5p in the NSCLC undergoing treatment with Everolimus. We confirmed that Everolimus targeted mTORC1 inducing NSCLC cells to secrete miR-7-5p-loaded exosomes in Rab27A and Rab27B-dependent manners. Loss of intracellular miR-7-5p induced phosphorylation of MNK/eIF4E axis, but a supplement of extra exosomal miR-7-5p could reverse it. Of note, both low expression of miR-7-5p and elevated MNK1 protein were associated with a poor prognosis of NSCLC. Both endogenous miR-7-5p and exo-miR-7-5p enhanced the therapeutic efficacy of Everolimus by inhibiting the proliferation, migration, and metastasis of NSCLC in vitro and in vivo. The combination of miR-7-5p with Everolimus induced apoptosis to exhibit a synergistic anticancer therapeutic efficacy through dual abrogation of MNK/eIF4E and mTOR in NSCLC. In conclusion, Everolimus decreases the intracellular miR-7-5p by releasing of miR-7-5p loaded exosomes from NSCLC cells in Rab27A and Rab27B dependent manners. Either endogenous miR-7-5p or exo-miR-7-5p combined with Everolimus can enhance the anticancer efficacy by targeting MNK/eIF4E axis and mTOR. Besides, both low levels of miR-7-5p and positive expression of MNK1 act as independent poor prognostic biomarkers for NSCLC. Therefore, restoring miR-7-5p carried by exosome may be a promising novel combined therapeutic strategy with Everolimus for NSCLC.
Many cancers evade immune surveillance by overexpressing PD-L1. PD-L1 interacted with its receptor PD-1, resulting in reduction of T cell proliferation and activation and thereafter cancer cell death ...mediated by T-lymphocyte. Understanding the mechanisms that regulate PD-L1 was of vital importance for immune checkpoint blockade therapy (ICBT).
Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of USP22 upon PD-L1 and CSN5 by WB, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. B16-F10 cells were used to explore the role of USP22 on tumorigenesis and T cell cytotoxicity. The relationship between USP22 and PD-L1 expression was investigated by Immunohistochemistry analysis in human non-small cell lung cancer samples.
Our data showed that USP22 interacted with PD-L1 and promoted its stability. USP22 deubiquitinated PD-L1 and inhibited its proteasome degradation. Moreover, USP22 also interacted with CSN5 and stabilized CSN5 through deubiquitination. Either USP22 or CSN5 could facilitate the interaction of PD-L1 with the other one. Furthermore, USP22 removed K6, K11, K27, K29, K33 and K63-linked ubiquitin chain of both CSN5 and PD-L1. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples.
Here, we suggested that USP22 is a new regulator for PD-L1. On the one hand, USP22 could directly regulate PD-L1 stability through deubiquitination. On the other hand, USP22 regulated PD-L1 protein level through USP22-CSN5-PD-L1 axis. In addition, USP22 depletion inhibited tumorigenesis and promoted T cell cytotoxicity. Besides, USP22 expression positively correlated with PD-L1 expression in human non-small cell lung cancer samples. Together, we identified a new regulator of PD-L1 and characterized the important role of USP22 in PD-L1 mediated immune evasion. Targeting USP22 might be a new solution to ICBT. Video abstract.
Nasopharyngeal carcinoma (NPC) is the malignant tumor arising from the nasopharynx epithelium with ethnic and geographical distribution preference. Y-box binding protein-1 (YB1) is the highly ...expressed DNA/RNA-binding protein with cold shock domain, and enhanced YB1 expression was proved to be associated with many kinds of malignant tumors. There is no systematic study about the regulation of YB1 and cell proliferation, migration, invasion and stress granules (SGs) in NPC, and the relationship between YB1 expression and clinical characteristics and prognosis of NPC patients. We analyzed the mRNA expression of YBX1 in head and neck squamous carcinoma (HNSC) and NPC in databases, investigated the functions of YB1 in cell proliferation, migration and invasion and SGs formation of NPC cells, and detected expression of YB1 protein in a large scale of NPC samples and analyzed their association with clinicopathological features and prognostic significance of NPC patients. YBX1 mRNA was significantly high expression in HNSC and NPC by bioinformatic analysis, and higher expression of YBX1 mRNA indicated poorer prognosis of HNSC patients. Clinically, the expression of YB1 in NPC tissues was significantly higher than these in the control nasopharyngeal epithelial tissues. We further found that the expression of YB1 had an evidently positive relation with advanced clinical stages of patients with NPC. The overall survival rates (OS) were significantly lower for NPC patients with positive expression of YB1. Multivariate analysis confirmed that positive expression of YB1 was the independent poorer prognostic factor for patients with NPC. Moreover, compared with the immortalized nasopharyngeal epithelial cell line (NP69), the basal level of YB1 in NPC cell lines was significantly higher. Knocking down YB1 may inhibit Akt/mTOR pathway in NPC cells. Knocking down YB1 by small interfering RNAs can reduce the ability of proliferation, migration, invasion and SGs formation of NPC cells. The expression of YB1 in NPC cell lines or patients with NPC was significantly higher. The high expression of YB1 protein may act as one valuable independent biomarker to predict poor prognosis for patients with NPC. Knocking down YB1 may release the malignant phenotype of NPC cells.
Immunotherapies in tumors have attracted increasing attention. They play an important role in precision medicine. Many immune-checkpoint inhibitors (ICIs) have obtained FDA approval and show good ...performance in the clinic. Hyperprogressive disease (HPD) after ICIs was first described in November 2016. Since then, a series of cases of HPD after ICIs have been reported. Notwithstanding that only a small subset of patients may experience this atypical response, HPD in affected patients means shorter survival times and worse prognoses. We summarized common standards for HPD diagnosis and profiled advantages and disadvantages. Elderly age,
family amplification, infiltration of PD-1-positive regulatory effector T cells and M2-like macrophages, and cancer stem cells may take part in HPD occurrence. Overall, we should focus on investigating the early markers and pathogenic mechanisms of HPD to solve this issue in ICIs.
Osimertinib (AZD9291 or TAGRISSO) is a promising and approved third-generation EGFR tyrosine kinase inhibitor (TKI) for treating patients with advanced non-small cell lung cancer (NSCLC) harboring ...EGFR-activating mutations or the resistant T790M mutation. However, the inevitable emergence of acquired resistance limits its long-term efficacy. A fuller understanding of the mechanism of action of osimertinib and its linkage to acquired resistance will enable the development of more efficacious therapeutic strategies. Consequently, we have identified a novel connection between osimertinib or other EGFR-TKIs and c-Myc. Osimertinib rapidly and sustainably decreased c-Myc levels primarily via enhancing protein degradation in EGFR-mutant (EGFRm) NSCLC cell lines and xenograft tumors. c-Myc levels were substantially elevated in different EGFRm NSCLC cell lines with acquired resistance to osimertinib in comparison with their corresponding parental cell lines and could not be reduced any further by osimertinib. Consistently, c-Myc levels were elevated in the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment compared with their corresponding untreated baseline c-Myc levels. Suppression of c-Myc through knockdown or pharmacologic targeting with BET inhibitors restored the response of resistant cell lines to osimertinib. These findings indicate that c-Myc modulation mediates the therapeutic efficacy of osimertinib and the development of osimertinib acquired resistance. Furthermore, they establish c-Myc as a potential therapeutic target and warrant clinical testing of BET inhibition as a potential strategy to overcome acquired resistance to osimertinib or other EGFR inhibitors. SIGNIFICANCE: This study demonstrates a critical role of c-Myc modulation in mediating therapeutic efficacy of osimertinib including osimertinib acquired resistance and suggests targeting c-Myc as a potential strategy to overcome osimertinib acquired resistance.
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