Molecular landmarks of tumor disulfidptosis across cancer types to promote disulfidptosis-target therapy.

The mystery about the mechanistic basis of disulfidptosis has recently been unraveled and shows promise as an effective treatment modality for triggering cancer cell death. However, the limited understanding of the role of disulfidptosis in tumor progression and drug sensitivity has hindered the development of disulfidptosis-targeted therapy and combinations with other therapeutic strategies. Here, we established a disulfidptosis signature model to estimate tumor disulfidptosis status in approximately 10,000 tumor samples across 33 cancer types and revealed its prognostic value. Then, we characterized disulfidptosis-associated molecular features and identified various types of molecular alterations that correlate with both drug-resistant and drug-sensitive responses to anti-tumor drugs. We further showed the vast heterogeneity in disulfidptosis status among 760 cancer cell lines across 25 cancer types. We experimentally validated that disulfidptosis score-high cell lines are more susceptible to glucose starvation-induced disulfidptosis compared to their counterparts with low scores. Finally, we investigated the impact of disulfidptosis status on drug response and revealed that disulfidptosis induction may enhance sensitivity to anti-cancer drugs, but in some cases, it could also lead to drug resistance in cultured cells. Overall, our multi-omics analysis firstly elucidates a comprehensive profile of disulfidptosis-related molecular alterations, prognosis, and potential therapeutic therapies at a pan-cancer level. These findings may uncover opportunities to utilize multiple drug sensitivities induced by disulfidptosis, thereby offering practical implications for clinical cancer therapy.

Circadian gene ARNTL initiates circGUCY1A2 transcription to suppress non-small cell lung cancer progression via miR-200c-3p/PTEN signaling.

BACKGROUND: As a subclass of endogenous stable noncoding RNAs, circular RNAs are beginning to be appreciated for their potential as tumor therapeutics. However, the functions and mechanisms by which circRNAs exert protective functions in non-small cell lung cancer (NSCLC) remain largely elusive. METHODS: The prognostic role of circGUCY1A2 was explored in lung adenocarcinoma specimens. The overexpressed and knockdown plasmids were used to evaluate the effect of circGUCY1A2 on NSCLC cell proliferation and apoptosis efficacy. Luciferase reporter system is used to prove that circGUCY1A2 could bind to miRNA. Chip-PCR was used to prove that circGUCY1A2 could be initiated by transcription factors ARNTL. Subcutaneous tumorigenicity grafts models were established to validate findings in vivo. RESULTS: The expression of circGUCY1A2 were significantly reduced (P < 0.001) and negatively correlated with tumor size (P < 0.05) in non-small cell lung cancer (NSCLC). CircGUCY1A2 upregulation promoted apoptosis and inhibits cell proliferation and growth of subcutaneous tumorigenicity grafts in nude mice (P < 0.01). In addition, intra-tumor injection of pLCDH-circGUCY1A2 inhibited tumor growth in patient-derived NSCLC xenograft models (PDX). Mechanism studies showed that circGUCY1A2 could act as a sponge to competitively bind miR-200c-3p, promote PTEN expression, and thereby inhibit PI3K/AKT pathway. In addition, we found that the circadian gene ARNTL, which was reduced in NSCLC and prolonged the overall survival of patients, could bind to the promoter of circGUCY1A2, thereby increasing its expression. CONCLUSIONS: This study is an original demonstration that ARNTL can inhibit the development of lung adenocarcinoma through the circGUCY1A2/miR-200c-3p/PTEN axis, and this finding provides potential targets and therapeutic approaches for the treatment of lung adenocarcinoma.

tRNA Modifications and Modifying Enzymes in Disease, the Potential Therapeutic Targets.

tRNA is one of the most conserved and abundant RNA species, which plays a key role during protein translation. tRNA molecules are post-transcriptionally modified by tRNA modifying enzymes. Since high-throughput sequencing technology has developed rapidly, tRNA modification types have been discovered in many research fields. In tRNA, numerous types of tRNA modifications and modifying enzymes have been implicated in biological functions and human diseases. In our review, we talk about the relevant biological functions of tRNA modifications, including tRNA stability, protein translation, cell cycle, oxidative stress, and immunity. We also explore how tRNA modifications contribute to the progression of human diseases. Based on previous studies, we discuss some emerging techniques for assessing tRNA modifications to aid in discovering different types of tRNA modifications.

Development and validation of a novel immune-related prognostic signature in lung squamous cell carcinoma patients.

Lung Squamous Cell Carcinoma (LUSC) is an aggressive malignancy with limited therapeutic options. The response to immune therapy is a determining factor for the prognosis of LUSC patients. This study aimed to develop a reliable immune-related prognostic signature in LUSC. We extracted gene expression and clinical data of LUSC from The Cancer Genome Atlas (TCGA). A total of 502 patients enrolled and were divided into respond and non-responder groups by the TIDE algorithm. The CIBERSORT algorithm and the LM22 gene signature were used to analyze the distribution of immune cells in LUSC. Efficacy and response strength of immunotherapy are calculated by the tumor mutation burden (TMB) and ESTIMATE Score. Differentially expressed genes (DEGs) between the two groups were analyzed. The differential expression genes related to overall survival were pointed as hub DEGs, and a prognostic signature was constructed with lasso regression analysis. LUSC patients were divided into responder and non-responder groups based on the response to immunotherapy. The distribution of immune cells was significantly different between the two groups. Forty-four DGEs were considered as overall survival-related genes. A prognostic signature was constructed, consisting of 11 hub-DGEs, including MMP20, C18orf26, CASP14, FAM71E2, OPN4, CGB5, DIRC1, C9orf11, SPATA8, C9orf144B, and ZCCHC5. The signature can accurately distinguish LUSC patients into high and low-risk groups. Moreover, the high-risk group had a shorter survival time than the low-risk group. The area under the ROC curve was 0.67. The multivariate Cox regression showed that the risk score calculated by the constructed signature was an independent prognostic predictor for LUSC patients. In short, we established a novel immune-related prognostic signature in LUCS, which has significant sensitivity and accuracy in predicting the prognosis of patients. Our research can guide the evaluation of the prognosis of LUSC patients in clinical, and the discovered immune-related genes can provide a theoretical basis for the discovery of new therapeutic targets.

SOCS5 knockdown suppresses metastasis of hepatocellular carcinoma by ameliorating HIF-1α-dependent mitochondrial damage.

The Pringle maneuver (PM) is widely used during hepatocellular carcinoma (HCC) resection. However, it inevitably leads to ischemia and hypoxia, which promotes tumor metastasis. In this study, immunohistochemical staining of specimens from 130 HCC patients revealed that long-time PM significantly affected the prognosis of patients with high expression of suppressor of cytokine signaling 5 (SOCS5), but did not affect the prognosis of patients with low expression of SOCS5. The TCGA database showed that patients with high expression of SOCS5 had higher hypoxia scores, and it was proved that SOCS5 could promote the expression of hypoxia-inducible factor 1 subunit alpha (HIF-1α) protein by clinical tissue samples, cell experiments, lung metastases, and subcutaneous tumorigenesis experiments. Then, we used CoCl2 to construct a hypoxia model, and confirmed that SOCS5 knockdown resisted hypoxia-induced mitochondrial damage by inhibiting the expression of HIF-1α, thereby inhibiting the invasion and migration of HCC cells by immunofluorescence, electron microscopy, migration, invasion, and other experiments. We performed rescue experiments using LY294002 and rapamycin and confirmed that the knockdown of SOCS5-inhibited HCC cell invasion and migration by inhibiting the PI3K/Akt/mTOR/HIF-1α signaling axis. More importantly, we obtained consistent conclusions from clinical, cellular, and animal studies that the hypoxia-induced invasion and migration ability of SOCS5-inhibited HCC were weaker than that of normal HCC. In conclusion, we identified a novel role for SOCS5 in regulating HIF-1α-dependent mitochondrial damage and metastasis through the PI3K/Akt/mTOR pathway. The development of a SOCS5-specific inhibitor, an indirect inhibitor of HIF-1α, might be effective at controlling PM-induced tumor micrometastases during HCC resection.

Recognition of immune-related tumor antigens and immune subtypes for mRNA vaccine development in lung adenocarcinoma.

Background: There are currently no treatments targeting the immune microenvironment (TME) as an extension of immunotherapy. Our research aims to provide guidance for the development of immune-related mRNA vaccines and the identification of immune subtypes for vaccine treatment in lung adenocarcinoma (LUAD). Methods: HTRNA-Seq and single cell RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO, GSE87340, GSE140343, GSE148071) databases. Immune checkpoints (ICP) were used as criteria to differentiate immune subtypes and immune resistance score (IRS) system is constructed by ssGSEA to judge the immune microenvironment status of patients. Results: Two overexpressed tumor-specific antigens, including ZC3H12D and TXNDC5, were found to be associated with both disease-free survival (DFS) and overall survival (OS). In addition, the expression of two genes correlated with antigen-presenting cell (APC) infiltration and tumor purity. Subsequently, the immune subtype of the patient was defined by constructing an IRS scoring system. The lower the IRS, the stronger the immune response in the TME. This result was verified in external datasets and at the single-cell level. Conclusions: ZC3H12D and TXNDC5 are potential tumor-specific antigens for developing mRNA vaccines in LUAD. Importantly, patients with low IRS are more suitable for the use of immunotherapy and vaccines. Our research enhances understanding of TME features and guides more effective immunotherapy strategies.

Alternative Splicing-Based Differences Between Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: Genes, Immune Microenvironment, and Survival Prognosis.

Alternative splicing (AS) event is a novel biomarker of tumor tumorigenesis and progression. However, the comprehensive analysis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is lacking. Differentially expressed analysis was used to identify the differentially expressed alternative splicing (DEAS) events between HCC or ICC tissues and their normal tissues. The correlation between DEAS events and functional analyses or immune features was evaluated. The cluster analysis based on DEAS can accurately reflect the differences in the immune microenvironment between HCC and ICC. Forty-five immune checkpoints and 23 immune features were considered statistically significant in HCC, while only seven immune checkpoints and one immune feature in ICC. Then, the prognostic value of DEAS events was studied, and two transcripts with different basic cell functions (proliferation, cell cycle, invasion, and migration) were produced by ADHFE1 through alternative splicing. Moreover, four nomograms were established in conjunction with relevant clinicopathological factors. Finally, we found two most significant splicing factors and further showed their protein crystal structure. The joint analysis of the AS events in HCC and ICC revealed novel insights into immune features and clinical prognosis, which might provide positive implications in HCC and ICC treatment.

tRNA-derived small RNAs: novel regulators of cancer hallmarks and targets of clinical application.

tRNAs are a group of conventional noncoding RNAs (ncRNAs) with critical roles in the biological synthesis of proteins. Recently, tRNA-derived small RNAs (tsRNAs) were found to have important biological functions in the development of human diseases including carcinomas, rather than just being considered pure degradation material. tsRNAs not only are abnormally expressed in the cancer tissues and serum of cancer patients, but also have been suggested to regulate various vital cancer hallmarks. On the other hand, the application of tsRNAs as biomarkers and therapeutic targets is promising. In this review, we focused on the basic characteristics of tsRNAs, and their biological functions known thus far, and explored the regulatory roles of tsRNAs in cancer hallmarks including proliferation, apoptosis, metastasis, tumor microenvironment, drug resistance, cancer stem cell phenotype, and cancer cell metabolism. In addition, we also discussed the research progress on the application of tsRNAs as tumor biomarkers and therapeutic targets.

XBP1- IGFBP3 Signaling Pathway Promotes NSCLC Invasion and Metastasis.

Lung cancer is the most frequently diagnosed cancer and the main cause of cancer death in the world. X-box binding protein 1 (XBP1), which is an important transcription factor involved in regulating the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, might act as a potent oncogenic protein in the processes of tumorigenesis, tumor proliferation and metastasis in various cancers. However, the clinical significance and pathological role of XBP1 in non-small cell lung cancer (NSCLC) remains unknown. In this study, we investigated the expression of XBP1s protein in the 104 NSCLC tumor tissues and matched adjacent normal lung tissues (ANLT) by Immunohistochemical (IHC), and we found overexpressed XBP1s protein was associated with NSCLC TNM stages, lymph node metastasis and poor prognosis. The further gain-and loss-of-function experiments indicated overexpression of XBP1s protein promoted cell invasion, migration and metastasis both in vitro and in vivo. Further study showed XBP1s protein could upregulate insulin-like growth factor binding protein-3 (IGFBP3) expression, and regulated NSCLC cells invasion and metastasis by regulating IGFBP3. Taken together, XBP1s protein is markedly overexpressed in NSCLC and serves as an oncogene that play a critical role in NSCLC tumorigenesis and development. Importantly, XBP1s protein might not only be a potential biomarker for metastasis and prognosis but also a potential therapeutic target in NSCLC.

Systematic Analyses of the Differentially Expressed Alternative Splicing Events in Gastric Cancer and Its Clinical Significance.

Accumulation of evidence has indicated a close relationship between alternative splicing (AS) and gastric cancer (GC), whereas systematic analyses of the differentially expressed AS events (DEAS) between GC and normal tissues are lacking. RNA-Seq data and the corresponding clinical information were downloaded from TCGA GC cohort. The percent spliced-in (PSI) value calculated in the GC tissues and normal tissues was employed to quantify the DEAS. Further, survival-associated DEAS and DEAS signatures were identified by univariate and multivariate cox regression analyses. To evaluate the association between DEAS and patients' clinical features, Kaplan-Meier analysis, receiver operator characteristic (ROC) curve, Cox proportional regression and nomograms incorporating the DEAS signatures were performed. DEAS and their splicing networks were finally analyzed by bioinformatics methods. In addition, we use the method of random grouping to divide the samples into the training group and the test group. The final results of the two groups are consistent. After strict filtering, a total of 44,935 AS events were identified, among which 11,141 DEAS were preliminarily screened from 5032 genes. A total of 454 DEAS was associated with OS, and 872 DEAS were associated with DFS. The final prognostic signatures were constructed from the survival-associated DEAS with an area under the receiver operating characteristic (ROC) curve (AUC) greater than 0.6. Only ES in ABI1 was simultaneously associated with OS and DFS. Finally, we identified the splicing correlation network between the prognostic splicing factors (SF) and DEAS in GC. Our study provided a systematic portrait of survival-associated DEAS in GC and uncovered splicing networks that are valuable in deciphering the underlying mechanisms of AS in GC.

The safety and efficacy of lenvatinib combined with immune checkpoint inhibitors therapy for advanced hepatocellular carcinoma.

China has one of the highest incidence rates of hepatocellular carcinoma (HCC) in the world. As most patients are diagnosed with advanced or unretractable HCC, systematic therapy is still the main treatment method for HCC. Currently, tyrosine kinase inhibitors (TKIs) and Immune checkpoint inhibitors (ICIs) are both the chief systematic therapy. And some studies have shown that the combination of TKIs and ICIs is more effective than monotherapy. The purpose of this review is to outline the rationale for the combination between lenvatinib and anti-PD-1(programmed cell death 1) and clinical trials to support this "golden combination". We also discuss the commonly treatment-emergent adverse events (AEs) and solutions for the patients with HCC who received the combination between lenvatinib and anti-PD-1 antibodies. Finally, we focus on the novel approaches, future perspectives and potential challenges about the combination of TKIs and ICIs.

A Review About Pembrolizumab in First-Line Treatment of Advanced NSCLC: Focus on KEYNOTE Studies.

 Lung cancer is currently the malignant tumor with the highest incidence and mortality in the world, while non-small cell lung cancer (NSCLC) is the most common pathological type of lung caner. In the past few decades, the only treatment options available for advanced NSCLC patients have been targeted therapy or chemotherapy, but these therapies are inevitably tolerated by tumors.  The discovery of immune checkpints that mediate the immune escape of tumor cells have been promoting a series of immune checkpoint inhibitors to be used in cancer treatment and achieved great results. Among them, pembrolizumab is currently the only PD-1 inhibitor approved for first-line treatment of NSCLC, whether it is monotherapy or combination therapy, for creditable performance in KEYNOTE studies. In this review, we systematically integrate the latest series of clinical trial results, pharmacological mechanisms, adverse events (AEs) and predictive biomarkers in the first-line treatment of NSCLC. We hope pembrolizumab could become a better choice for more clinicians and benefit more patients with advanced NSCLC.

Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC.

Lung cancer is currently the highest morbidity and mortality malignancy all over the world. In the past, the treatment options available for patients with lung cancer were mainly chemotherapy and tyrosine kinase inhibitors, but after a period of treatment, cancer cells inevitably developed resistance. With the elucidation of the immune escape mechanism of tumor cells recently, immunotherapy, especially immune checkpoint inhibitors, has shown unparalleled advantages in cancer treatment, becoming a new hope for cancer patients after multi-line treatment failure. Immune checkpoint inhibitors usually belong to monoclonal PD-1 or PD-L1 antibody. Pembrolizumab is one of the first immune checkpoint inhibitors approved by the FDA to treat NSCLC and is currently the only immunotherapy drug approved for first-line treatment of NSCLC in immune checkpoint inhibitors. However, there are still some problems to be solved in the clinical application of immune checkpoint inhibitors, such as the lack of effective biomarkers to predict efficacy. Therefore, in this review, we systematically summarize the possible biomarkers that can affect the efficacy of immune checkpoint inhibitors such as PD-L1 expression and tumor mutation burden.

Survival-associated alternative splicing signatures in non-small cell lung cancer.

Alternative splicing (AS) is fundamental to transcriptome and proteome richness, and data from recent studies suggested a critical association between AS and oncogenic processes. To date, no systematic analysis has been conducted on AS from the perspective of different sexes and subtypes in non-small-cell lung cancer (NSCLC). Thus, we integrated the information of NSCLC patients from The Cancer Genome Atlas (TCGA) and evaluated AS profiles from the perspectives of sex and subtype. Eventually, a total of 813 and 1020 AS events were found to be significantly related to the overall survival (OS) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. Four prognostic prediction models performed well at 1, 3, and 5 years, with an area under the receiver operating characteristic (ROC) curve (AUC) greater than 0.75. Notably, we explored the upstream splicing factors (SFs) and downstream regulatory mechanisms of the OS-associated AS events and verified four differentially expressed alternative splicing (DEAS) events via qPCR. These findings can provide important guidance for subsequent studies. In addition, we also constructed nomograms to facilitate early screening by clinicians and to determine patient outcomes in NSCLC.

The role of RICTOR amplification in targeted therapy and drug resistance.

The emergence of tyrosine kinase inhibitors (TKIs) has changed the current treatment paradigm and achieved good results in recent decades. However, an increasing number of studies have indicated that the complex network of receptor tyrosine kinase (RTK) co-activation could influence the characteristic phenotypes of cancer and the tumor response to targeted treatments. One of strategies to blocking RTK co-activation is targeting the downstream factors of RTK, such as PI3K-AKT-mTOR pathway. RICTOR, a core component of mTORC2, acts as a key effector molecule of the PI3K-AKT pathway; its amplification is often associated with poor clinical outcomes and resistance to TKIs. Here, we discuss the biology of RICTOR in tumor and the prospects of targeting RICTOR as a complementary therapy to inhibit RTK co-activation.

Identification and validation of key genes with prognostic value in non-small-cell lung cancer via integrated bioinformatics analysis.

BACKGROUND: Lung cancer is the most common cause of cancer-related death among all human cancers and the five-year survival rates are only 23%. The precise molecular mechanisms of non-small cell lung cancer (NSCLC) are still unknown. The aim of this study was to identify and validate the key genes with prognostic value in lung tumorigenesis. METHODS: Four GEO datasets were obtained from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) were selected for Kyoto Encyclopedia of Genes and Genomes pathway analysis and Gene Ontology enrichment analysis. Protein-protein interaction (PPI) networks were constructed using the STRING database and visualized by Cytoscape software and Molecular Complex Detection (MCODE) were utilized to PPI network to pick out meaningful DEGs. Hub genes, filtered from the CytoHubba, were validated using the Gene Expression Profiling Interactive Analysis database. The expressions and prognostic values of hub genes were carried out through Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter. Finally, quantitative PCR and the Oncomine database were used to verify the differences in the expression of hub genes in lung cancer cells and tissues. RESULTS: A total of 121 DEGs (49 upregulated and 72 downregulated) were identified from four datasets. The PPI network was established with 121 nodes and 588 protein pairs. Finally, AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 were selected by Cytohubba, and they all correlated with worse overall survival (OS) in NSCLC. CONCLUSION: The results showed that AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 may be critical genes in the development and prognosis of NSCLC. KEY POINTS: Our results indicated that AURKA, KIAA0101, CDC20, MKI67, CHEK1, HJURP, and OIP5 may be critical genes in the development and prognosis of NSCLC. Our methods showed a new way to explore the key genes in cancer development.

Effect and biomarker of Nivolumab for non-small-cell lung cancer.

In recent years, immunotherapy has become an innovative technology for cancer therapy with the discovery of immunological checkpoints. It has shown great potential in a variety of advanced cancer treatments. Particularly, significant progress has been achieved in the understanding of programmed death-1/programmed death ligand-1 (PD-1/ PD-L1) pathway. Nivolumab, a human immunoglobulin (Ig)G4 PD-1 monoclonal antibody, was the first PD-1 inhibitor approved in the treatment of advanced non-small-cell lung cancer (NSCLC). Nivolumab has become a mainstay of first-line treatment of advanced/metastatic NSCLC without targetable genetic alterations. However, there are some questions in clinic that lacking of identifying biomarkers to predict the PD-1 immune checkpoint inhibition response. In this review, we summarize the results from recent clinical trials that have evaluated the nivolumab as first- or second- line treatment as monotherapy, in combination with chemotherapy and other immunotherapies. Also, we discuss the function of potential predicted biomarkers such as PD-L1 expression and tumor mutation burden in cancer treatment.

Progress in the treatment of solid tumors with apatinib: a systematic review.

With the investigation of molecular targets, many agents, such as trastuzumab and ramucirumab, have attained a positive outcome in oncotherapy. Vascular endothelial growth factor (VEGF) is considered a potent factor in angiogenesis and plays an important role in the growth of tumors. Moreover, both VEGF and its receptor are usually excessively expressed in solid tumors and could be hopeful targets for the treatment of neoplasms. Apatinib (YN968D1) is an oral small-molecule tyrosine kinase inhibitor of VEGFR-2. By inhibiting several signaling transduction pathways, it restrains angiogenesis and subsequently controls tumorigenesis. According to current studies, apatinib shows promising application in various solid tumors as a post-second- and post-third-line treatment. It could significantly improve the median overall survival and progression-free survival of patients with tolerated adverse reactions. This paper aims to summarize the recent research on apatinib including the mechanism, pharmacokinetics, trials, adverse reactions, and prospect as a treatment.