Cancer-related Functions Research Articles

Alternative splicing in the genome of HPV and its regulation.

Persistent infection with high-risk human papillomavirus (HR-HPV) is the main cause of cervical cancer. These chronic infections are characterized by high expression of the HPV E6 and E7 oncogenes and the absence of the L1 and L2 capsid proteins. The regulation of HPV gene expression plays a crucial role in both the viral life cycle and rare oncogenic events. Alternative splicing of HPV mRNA is a key mechanism in post-transcriptional regulation. Through alternative splicing, HPV mRNA is diversified into various splice isoforms with distinct coding potentials, encoding multiple proteins and influencing the expression of HPV genes. The spliced mRNAs derived from a donor splicing site within the E6 ORF and one of the different acceptor sites located in the early mRNA contain E6 truncated mRNAs, named E6*. E6* is one of the extensively studied splicing isoforms. However, the role of E6* proteins in cancer progression remains controversial. Here, we reviewed and compared the alternative splicing events occurring in the genomes of HR-HPV and LR-HPV. Recently, new HPV alternative splicing regulatory proteins have been continuously discovered, and we have updated the regulation of HPV alternative splicing. In addition, we summarized the functions of known splice isoforms from three aspects: anti-tumorigenic, tumorigenic, and other cancer-related functions, including not only E6*, but also E6^E7, E8^E2, and so on. Comprehending their contributions to cancer development enhances insights into the carcinogenic mechanisms of HPV and explores the potential utility of alternative splicing in the diagnosis and treatment of cervical cancer.

Regulatory effect of N6-methyladenosine on tumor angiogenesis.

Previous studies have demonstrated that genetic alterations governing epigenetic processes frequently drive tumor development and that modifications in RNA may contribute to these alterations. In the 1970s, researchers discovered that N6-methyladenosine (m6A) is the most prevalent form of RNA modification in advanced eukaryotic messenger RNA (mRNA) and noncoding RNA (ncRNA). This modification is involved in nearly all stages of the RNA life cycle. M6A modification is regulated by enzymes known as m6A methyltransferases (writers) and demethylases (erasers). Numerous studies have indicated that m6A modification can impact cancer progression by regulating cancer-related biological functions. Tumor angiogenesis, an important and unregulated process, plays a pivotal role in tumor initiation, growth, and metastasis. The interaction between m6A and ncRNAs is widely recognized as a significant factor in proliferation and angiogenesis. Therefore, this article provides a comprehensive review of the regulatory mechanisms underlying m6A RNA modifications and ncRNAs in tumor angiogenesis, as well as the latest advancements in molecular targeted therapy. The aim of this study is to offer novel insights for clinical tumor therapy.

M2 macrophage-derived lncRNA NORAD in EVs promotes NSCLC progression via miR-520g-3p/SMIM22/GALE axis

Non-small cell lung cancer (NSCLC) constitutes the majority of lung cancer cases, accounting for over 80%. RNAs in EVs play a pivotal role in various biological and pathological processes mediated by extracellular vesicle (EV). Long non-coding RNAs (lncRNAs) are widely associated with cancer-related functions, including cell proliferation, migration, invasion, and drug resistance. Tumor-associated macrophages are recognized as pivotal contributors to tumorigenesis. Given these insights, this study aims to uncover the impact of lncRNA NORAD in EVs derived from M2 macrophages in NSCLC cell lines and xenograft mouse models of NSCLC. EVs were meticulously isolated and verified based on their morphology and specific biomarkers. The interaction between lncRNA NORAD and SMIM22 was investigated using immunoprecipitation. The influence of SMIM22/GALE or lncRNA NORAD in EVs on glycolysis was assessed in NSCLC cell lines. Additionally, we evaluated the effects of M2 macrophage-derived lncRNA NORAD in EVs on cell proliferation and apoptosis through colony formation and flow cytometry assays. Furthermore, the impact of M2 macrophage-derived lncRNA NORAD in EVs on tumor growth was confirmed using xenograft tumor animal models. The results underscored the potential role of M2 macrophage-derived lncRNA NORAD in EVs in NSCLC. SMIM22/GALE promoted glycolysis and the proliferation of NSCLC cells. Furthermore, lncRNA NORAD in EVs targeted SMIM22 and miR-520g-3p in NSCLC cells. Notably, lncRNA NORAD in EVs promoted the proliferation of NSCLC cells and facilitated NSCLC tumor growth through the miR-520g-3p axis. In conclusion, M2 macrophage-derived lncRNA NORAD in EVs promotes NSCLC progression through the miR-520g-3p/SMIM22/GALE axis.

Biological and clinical relevance of correlated expression levels of coding and long noncoding RNAs in HPV16 positive cervical cancers

Human papillomavirus (HPV) drives cervical cancer (CaCx) pathogenesis and viral oncoproteins jeopardize global gene expression in such cancers. In this study, our aim was to identify differentially expressed coding (DEcGs) and long noncoding RNA genes (DElncGs) specifically sense intronic and Natural Antisense Transcripts as they are located in the genic regions and may have a direct influence on the expression pattern of their neighbouring coding genes. We compared HPV16-positive CaCx patients (N = 44) with HPV-negative normal individuals (N = 34) by employing strand-specific RNA-seq and determined the relationships between DEcGs and DElncGs and their clinical implications. By performing Gene set enrichment and protein–protein interaction (PPI) analyses of DEcGs, we identified enrichment of processes crucial for abortive virus life cycle and cancer progression. The DEcGs formed 16 gene clusters which we identified through Molecular Complex Detection (MCODE) plugin of Cytoscape. All the gene clusters portrayed cancer-related functions. We recorded significantly correlated expression levels of 79 DElncGs with DEcGs at proximal genomic loci based on Pearson’s Correlation coefficients. Of these gene pairs, 24 pairs portrayed significantly altered correlation coefficients among patients, compared to normal individuals. Of these, 6 DEcGs of 6 such gene pairs, belonged to 5 of the identified gene clusters, one of which was survival-associated. Out of the 24 correlated DEcG: DElncG pairs, we identified 3 pairs, where expression of both members was significantly associated with patient overall survival. The findings justify the cooperative roles of these gene pairs, in patient prognostication, thereby bearing immense potential for translation. Thus, elucidation of correlative strengths between paired DElncGs and DEcGs in patient and normal samples, could serve as a foundation for identification of therapeutic and prognostic targets of HPV16-positive CaCx.Graphical abstract

EIF6 Promotes Gastric Cancer Proliferation and Invasion by Regulating Cell Cycle

ObjectiveTo investigate the role and function of eIF6 in gastric cancer (GC).MethodsThe expression level of eIF6 in GC tissues and normal tissues was detected in different high-throughput sequencing cohorts. Survival analysis, gene differential analysis, and enrichment analysis were performed in the TCGA cohort. Biological networks centered on eIF6 were constructed through two different databases. Immunohistochemistry (IHC) and Western blot were used to detect protein expression of eIF6, and qRT-PCR was used to detect eIF6 mRNA expression. The correlation between the expression of eIF6 in GC tissues and clinicopathological parameters of GC was analyzed. siRNA knockout of eIF6 was used to study the proliferation, migration, and invasion. The effects of eIF6 on cell cycle and Cyclin B1 were detected by flow cytometry and Western blot.ResultseIF6 was significantly overexpressed in GC tissues and predicted poor prognosis. In addition, 113 differentially expressed genes were detected in cancer-related biological pathways and functions by differential analysis. Biological networks revealed interactions of genes and proteins with eIF6. The expression intensity of eIF6 in cancer tissues was higher than that in adjacent tissues (P = 0.0001), confirming the up-regulation of eIF6 expression in GC tissues. The expression level of eIF6 was statistically significant with pTNM stage (P = 0.006). siRNA knockout of eIF6 significantly reduced the proliferation, colony formation, migration, and invasion ability of GC cells. Silencing of eIF6 also inhibited the cell cycle of GC cells in G2/M phase and decreased the expression level of CyclinB1.ConclusionOur study suggests that eIF6 is up-regulated in GC and may promote the proliferation, migration, and invasion of GC by regulating cell cycle.

Investigation of the Molecular Mechanisms of Sanguinaria canadensis in Treating Lung Cancer Using Network Pharmacology and Molecular Docking Techniques

This study examines the molecular mechanism that underlies the possible therapeutic benefits of Sanguinaria canadensis in the treatment of lung cancer. Through network pharmacology and molecular docking techniques, we identify 15 bioactive compounds from S. canadensis, with sanguinarine and chelerythrine being the most prominent. These compounds interact with key proteins involved in lung cancer progression, including IL-6, IL-1β, ICAM1, TNF, and MMP-9. Pathway enrichment analysis reveals significant involvement of pathways such as homologous recombination, p53 signaling, and cell cycle. GO and KEGG analyses elucidate the molecular mechanisms underlying cancer pathogenesis and highlight potential therapeutic targets. STING enrichment analysis uncovers crucial biological processes associated with STING-regulated genes, suggesting their involvement in cancer-related functions. Molecular docking studies demonstrate strong binding affinities between bioactive compounds and target proteins, indicating potential efficacy in impeding cancer-related processes. This comprehensive investigation provides insights into the therapeutic potential of S. canadensis in lung cancer treatment, warranting further experimental validation and exploration of novel therapeutic strategies.

Male breast cancer differs from female breast cancer in molecular features that affect prognoses and drug responses

BackgroundMale breast cancer (MBC) is a rare malignancy with a worse prognosis than female breast cancer (FBC). Current MBC treatment strategies are based on those for FBC. However, molecular differences between MBC and FBC with respect to prognosis and drug responses remain unclear. MethodsAfter controlling for confounding factors with propensity score matching (PSM), differences between MBC and FBC were comprehensively analyzed using many types of data: survival, immune microenvironments, sex hormone responses, drug sensitivity, transcriptomes, genomes, epigenomes, and proteomes. ResultsOverall survival (OS) and cancer-specific survival (CSS) were both worse for MBC than for FBC. Differentially expressed mRNAs were enriched in numerous cancer-related functions and pathways, with SPAG16 and STOX1 being as the most important prognosis-related mRNAs for MBC. Competing endogenous RNA (ceRNA) and transcription factor (TF)-mRNA regulatory networks contain potential prognostic genes. Nine genes had higher mutation frequencies in MBC than in FBC. MBC shows a comparatively poor response to immunotherapy, with five proteins that promote breast cancer progression being highly expressed in MBC. MBC may be more responsive than FBC to estrogen. We detected six United States Food and Drug Administration (FDA)-approved therapeutic target genes as being differentially expressed between MBC and FBC. ConclusionThe poor prognosis of MBC compared to FBC is due to numerous molecular differences and resulting drug responses.

Abstract 3258: A potential oncogenic role and immunoregulatory mechanisms of MZB1 in melanoma

Abstract While immune checkpoint blockade (ICB) therapies have drastically improved melanoma treatment, a majority of patients fail to achieve a durable response. Thus, there is a critical need to advance our understanding of melanoma immune evasion mechanisms and identify novel targets capable of enhancing ICB responses. MZB1 (Marginal Zone B and B1 Cell Specific Protein), an immune regulator gene, is differentially expressed in metastatic melanoma compared to primary melanoma or normal skin. In a limited number of cancers, MZB1 has been shown to function as either an oncogene or a tumor suppressor. However, its role and significance in melanoma is not known. In this study, we determined the functional significance and immunoregulatory mechanisms of MZB1 in human melanoma cell lines using MZB1 overexpression (OE) (in SK-MEL-2, and SK-MEL-28) and CRISPR knockout (KO) (in A375 and Hs294T) lines. MZB1 OE significantly increased melanoma cell proliferation and expression of the proliferation markers Ki67 and PCNA, while MZB1 KO yielded the opposite effect. To identify immunoregulatory mechanisms associated with MZB1, we performed differential gene expression analysis of 770 immune-related genes using NanoString nCounter technology. nSolver analysis identified 153 differentially expressed genes (DEGs) as a result of MZB1 knockout in Hs294T cells (adjusted p <0.05, 1.5-fold change cutoff). MZB1 KO strongly reduced the expression of the HLA class-II family genes and altered the expression of various cytokines, suggesting an immunoregulatory role of MZB1. Further, MZB1 KO significantly downregulated genes related to cancer progression and metastasis promotion. Additionally, MZB1 KO reduced expression of common “cancer stem cell” genes, such as RXRG, ALDH1A1, AQP1, NFATC2, LPAR1, indicating MZB1 expression in melanoma may promote a dedifferentiated or neural crest-like state. In addition, an Ingenuity Pathway Analysis (IPA) of the DEGs revealed many cancer-related functions altered upon MZB1 KO (p adjusted < 0.05) and displayed a negative enrichment for cancer-promoting pathways including tumor growth, metastasis, and proliferation. IPA regulatory analysis predicted MZB1 KO to decrease the activation of oncogenic signaling components including PI3K, MEK, and ERK1/2. Further, IPA predicted that MZB1 inhibition could positively sensitize melanoma cells towards higher immune responses by activating mechanisms associated with T cell proliferation and activation, leukocyte migration, and macrophage activation. Overall, our study suggests MZB1 promotes oncogenic signaling in melanoma to drive proliferation and dedifferentiation, as well as regulates a wide range of immune-related genes that may be responsible for immune evasion in melanoma cells. Thus, MZB1 merits further investigation to determine if the immune consequences yielded by targeting MZB1 can complement ICB approaches in the management of melanoma. Citation Format: Gagan Chhabra, Carl A. Shirley, Julia M. Krien, Mary A. Ndiaye, Nihal Ahmad. A potential oncogenic role and immunoregulatory mechanisms of MZB1 in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3258.

Has-miR-300-GADD45B promotes melanoma growth via cell cycle.

Response to oncogenic factors like UV, GADD45 family in skin participates in scavenging ROS, DNA repair and cell cycle control. Because of this, the previous study of the chronic UVB injury model has found that hsa-miR-300 can conduct intercellular transport by exosomes and target regulation of GADD45B. Whether the hsa-miR-300-GADD45B still regulates tumor development by cell cycle pathway is unclear. Through transcriptomic analysis of primary (n=39) and metastatic (n=102) melanoma, it was confirmed that in metastatic samples, some of the 97 down-regulated genes participate in maintaining skin homeostasis while 42 up-regulated genes were enriched in cancer-related functions. Furthermore, CDKN1A, CDKN2A, CXCR4 and RAD51 in the melanoma pathway, were also differentially expressed between normal skin and melanoma. CDKN1A and CDKN2A were also found to be involved in TP53-dependent cell cycle regulation. In conclusion, it was speculated that CDKN1A, CDKN2A, TP53, GADD45B and hsa-miR-300 may have regulatory relationships. It was demonstrated that there is a bidirectional regulation between hsa-miR-300 and TP53. In addition, miR-300 can regulate CDKN1A by GADD45B/TP53 and promote melanoma growth by accelerating the cell cycle transition from G1/S to G2 phase.

Dynamic alterations of the transcriptome-wide m6A methylome in cytogenetically normal acute myeloid leukaemia during initial diagnosis and relapse

Accumulating studies have indicated that N6-methyladenosine (m6A) plays an important role in acute myeloid leukaemia (AML). However, little is known about the m6A methylome at a transcriptome-wide scale in AML patients. We obtained three pairs of bone marrow (BM) samples from cytogenetically normal AML patients at the timepoints of diagnosis (AML) and relapse (R_AML) and three BM samples from healthy donors used as normal controls (NCs). Methylated RNA immunoprecipitation next-generation sequencing (MeRIP-Seq) was conducted to identify differences in the m6A methylomes between AML and NC and between R_AML and AML. We identified a total of 11,076 and 11,962 differential m6A peaks in AML and R_AML group, respectively. These dysregulated m6A peaks were detected on all chromosomes, especially chr1, chr19 and chr17, and were mainly enriched in 3′ untranslated regions, stop codon and coding sequence regions. Moreover, GO and KEGG analyses indicated that m6A -modified genes were significantly enriched in cancer-related biological functions and pathways. Additionally, we identified a link between the m6A methylome and RNA transcriptome via combined analyses of MeRIP-seq and RNA-seq data. In addition, 5 genes, HSPG2, HOMER3, TSPO2, CXCL12 and FUT1 regulated by m6A modification potentially, were shown to be related to the prognosis of AML patients. Additionally, we detected the mRNA expression of major m6A regulators and potential target mRNA on the leukemogenesis and found that the expression of IGF2BP2, HSPG2 and HOMER3 were upregulated in AML at the time of diagnosis. Moreover, their expression became downregulated after remission and then elevated again at relapse. Our study provides the first data on the differential m6A methylome in AML patients during initial diagnosis and relapse. This study demonstrates a novel relationship between m6A modification and AML relapse and paves the way for further studies aimed at elucidating the epigenic mechanisms involved in the relapse of AML.

Small extrachromosomal circular DNAs as biomarkers for multi-cancer diagnosis and monitoring.

Small extrachromosomal circular DNAs (eccDNAs) have the potential to be cancer biomarkers. However, the formation mechanisms and functions of small eccDNAs selected in carcinogenesis are not clear, and whether the small eccDNA profile in the plasma of cancer patients represents that in cancer tissues remains to be elucidated. A novel sequencing workflow based on the nanopore sequencing platform was used to sequence naturally existing full-length small eccDNAs in tissues and plasma collected from 25 cancer patients (including prostate cancer, hepatocellular carcinoma and colorectal cancer), and from an independent validation cohort (including 7 cancer plasma and 14 healthy plasma). Compared with those in non-cancer tissues, small eccDNAs detected in cancer tissues had a significantly larger number and size (P=0.040 and 2.2e-16, respectively), along with more even distribution and different formation mechanisms. Although small eccDNAs had different general characteristics and genomic annotation between cancer tissues and the paired plasma, they had similar formation mechanisms and cancer-related functions. Small eccDNAs originated from some specific genes had great multi-cancer diagnostic value in tissues (AUC ≥ 0.8) and plasma (AUC>0.9), especially increasing the accuracy of multi-cancer prediction of CEA/CA19-9 levels. The high multi-cancer diagnostic value of small eccDNAs originated from ALK&ETV6 could be extrapolated from tissues (AUC=0.804) to plasma and showed high positive predictive value (100%) and negative predictive value (82.35%) in a validation cohort. As independent and stable circular DNA molecules, small eccDNAs in both tissues and plasma can be used as ideal biomarkers for cost-effective multi-cancer diagnosis and monitoring.

Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3.

EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimabplusplatinum-doublet chemotherapy versus placebopluschemotherapy for first-line treatment of advanced non-small cell lung cancer. This study evaluated patient-reported outcomes (PROs). PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model. A total of 312 patients were assigned to receive cemiplimabplusplatinum-doublet chemotherapy and 154 to receive placebopluschemotherapy; 391 (83.9%) were male and the median age was 63.0years (range, 25-84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (-4.98, 95% confidence interval [CI] -8.36 to -1.60, p=.004) and a statistically significant delayin TTD (hazard ratio, 0.39; 95% CI, 0.26-0.60, p<.0001) favoring cemiplimabpluschemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimabpluschemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimabpluschemotherapy compared with nonsignificant overall change from baseline for placebopluschemotherapy (1.69, 95% CI, 0.20-3.19 vs. 1.08, 95% CI, -1.34 to 3.51; between arms, p=.673). No analyses yielded statistically significant PRO resultsfavoring placebopluschemotherapy for any QLQ-C30 or QLQ-LC13 scale. Cemiplimabpluschemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer-specific symptoms and functions.

A functional analysis of omic network embedding spaces reveals key altered functions in cancer.

Advances in omics technologies have revolutionized cancer research by producing massive datasets. Common approaches to deciphering these complex data are by embedding algorithms of molecular interaction networks. These algorithms find a low-dimensional space in which similarities between the network nodes are best preserved. Currently available embedding approaches mine the gene embeddings directly to uncover new cancer-related knowledge. However, these gene-centric approaches produce incomplete knowledge, since they do not account for the functional implications of genomic alterations. We propose a new, function-centric perspective and approach, to complement the knowledge obtained from omic data. We introduce our Functional Mapping Matrix (FMM) to explore the functional organization of different tissue-specific and species-specific embedding spaces generated by a Non-negative Matrix Tri-Factorization algorithm. Also, we use our FMM to define the optimal dimensionality of these molecular interaction network embedding spaces. For this optimal dimensionality, we compare the FMMs of the most prevalent cancers in human to FMMs of their corresponding control tissues. We find that cancer alters the positions in the embedding space of cancer-related functions, while it keeps the positions of the noncancer-related ones. We exploit this spacial 'movement' to predict novel cancer-related functions. Finally, we predict novel cancer-related genes that the currently available methods for gene-centric analyses cannot identify; we validate these predictions by literature curation and retrospective analyses of patient survival data. Data and source code can be accessed at https://github.com/gaiac/FMM.

Abstract 2676: Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine

Abstract Despite a plethora of therapeutic strategies, improved survival is only modest for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). Additionally, between 2000 and 2018, pancreatic cancer incidence significantly increased with the greatest increase among women ages 15-35 years. We identified a protoberberine alkaloid, Palmatine (PMT), that was effective in slowing tumor growth and improving therapeutic outcome of gemcitabine (GEM) in pancreatic tumor bearing mice. Interestingly, the improved therapeutic outcome with the combination was observed in a sex-associated manner in mice. Intriguingly, PMT reduced proliferation of cells isolated from surgically resected tumor samples in 71% of female and 33% of male pancreatic cancer patients. We also observed that the correlation between PMT effects on cancer-related biological functions was associated with downregulation of STAT3 signaling. RNA-seq data from STAT3-KD pancreatic cancer cells revealed enrichment of genes associated with fatty acid metabolism. Of these, mRNA expression of ELOVL2 (Elongation of Very Long Chain Fatty Acids-Like 2) was most significantly increased suggesting a negative regulatory role for STAT3 in ELOVL2 expression. In silico analysis of the pancreatic cancer UalcanPan database shows that ELOVL2 is significantly reduced in human pancreatic tumors relative to normal pancreas and that high expression of ELOVL2 is associated with increased survival. The fatty acid elongase, ELOVL2, is involved in the production of docahexaenoic acid (DHA). Our experimental data show that PMT increased ELOVL2 expression. Taken together, these findings suggest the potential utility of PMT in therapeutic sensitization of GEM through deregulation of STAT3-mediated ELOVL2 signaling. These observations further suggest a sex-associated role for PMT in improving outcomes that may in part involve ELOVL2 function. Supported in part through VA Merit Award BX003876 and Owens Foundation pilot (APK). Citation Format: Meagan Marie Ybarra, Xiaoyu Yang, Amanda Munoz, Michelle Villarreal, Joel Michalek, Li-Ju Wang, Yidong Chen, Ikeno Yuji, Glenn Halff, Susan Weintraub, Rita Gosh, Addanki P. Kumar. Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2676.

Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment

Immune checkpoint blockade (ICB) therapy targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients with pancreatic cancer remain resistant to ICB. Moreover, there is a lack of optimal biomarkers for the prediction of response to this therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, termed zinc finger Asp‐His‐His‐Cys-type palmitoyltransferases (ZDHHC), which precisely control various cancer-related protein functions and represent promising drug targets for cancer therapy. Here, we revealed that tumor cell-intrinsic ZDHHC9 was overexpressed in pancreatic cancer tissues and associated with impaired anti-tumor immunity. In syngeneic pancreatic tumor models, the knockdown of ZDHHC9 expression suppressed tumor progression and prolonged survival time of mice by modifying the immunosuppressive (‘cold’) to proinflammatory (‘hot’) tumor microenvironment. Furthermore, ZDHHC9 deficiency sensitized anti-PD-L1 immunotherapy mainly in a CD8+ T cell dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in pancreatic tumors. Collectively, our findings indicate that ZDHHC9 overexpression in pancreatic tumors is a mechanism involved in the inhibition of host anti-tumor immunity and highlight the importance of inactivating ZDHHC9 as an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy against pancreatic cancer.

High-Throughput Sequencing Reveals That Rotundine Inhibits Colorectal Cancer by Regulating Prognosis-Related Genes

Rotundine is an herbal medicine with anti-cancer effects. However, little is known about the anti-cancer effect of rotundine on colorectal cancer. Therefore, our study aimed to investigate the specific molecular mechanism of rotundine inhibition of colorectal cancer. MTT and cell scratch assay were performed to investigate the effects of rotundine on the viability, migration, and invasion ability of SW480 cells. Changes in cell apoptosis were analyzed by flow cytometry. DEGs were detected by high-throughput sequencing after the action of rotundine on SW480 cells, and the DEGs were subjected to function enrichment analysis. Bioinformatics analyses were performed to screen out prognosis-related DEGs of COAD. Followed by enrichment analysis of prognosis-related DEGs. Furthermore, prognostic models were constructed, including ROC analysis, risk curve analysis, PCA and t-SNE, Nomo analysis, and Kaplan-Meier prognostic analysis. In this study, we showed that rotundine concentrations of 50 μM, 100 μM, 150 μM, and 200 μM inhibited the proliferation, migration, and invasion of SW480 cells in a time- and concentration-dependent manner. Rotundine does not induce SW480 cell apoptosis. Compared to the control group, high-throughput results showed that there were 385 DEGs in the SW480 group. And DEGs were associated with the Hippo signaling pathway. In addition, 16 of the DEGs were significantly associated with poorer prognosis in COAD, with MEF2B, CCDC187, PSD2, RGS16, PLXDC1, HELB, ASIC3, PLCH2, IGF2BP3, CLHC1, DNHD1, SACS, H1-4, ANKRD36, and ZNF117 being highly expressed in COAD and ARV1 being lowly expressed. Prognosis-related DEGs were mainly enriched in cancer-related pathways and biological functions, such as inositol phosphate metabolism, enterobactin transmembrane transporter activity, and enterobactin transport. Prognostic modeling also showed that these 16 DEGs could be used as predictors of overall survival prognosis in COAD patients. Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of these prognosis-related genes. Our findings could further provide new directions for the treatment of colorectal cancer.

An omics-to-omics joint knowledge association subtensor model for radiogenomics cross-modal modules from genomics and ultrasonic images of breast cancers

The radiogenomics analysis can provide the connections between genomics and radiomics, which can infer the genomic features of tumors from their radiogenomic associations through the low-cost and non-invasiveness screening ultrasonic images. Although there are a number of pioneer approaches exploring the connections between genomic aberrations and ultrasonic features, these studies mainly focus on the relationship between ultrasonic features and only the most popular cancer genes, confronting two difficulties: missing many-to-many relationships as omics-to-omics view, and confounding group-specific associations with whole sample associations. To overcome the difficulty of omics-to-omics view and the issue of tumor heterogeneity, we propose an omics-to-omics joint knowledge association subtensor model. Specifically, the subtensor factorization framework can successfully discover the joint cross-modal module via an omics-to-omics view, while the sparse weight sample indication strategy can mine sample subgroups from the multi-omic data with tumor heterogeneity. The experimental evaluation result shows the jointness of the discovered modules across omics, their association with tumorigenesis contribution, and their relation for cancer related functions. In summary, our proposed omics-to-omics joint knowledge association subtensor model can serve as an efficient tool for radiogenomic knowledge associations, promoting the cross-modal knowledge graph construction of in explainable artificial intelligence cancer diagnosis.

Targeting BAP1 with small compound inhibitor for colon cancer treatment

BRCA1-associated protein-1 (BAP1) is a ubiquitin C-terminal hydrolase domain-containing deubiquitinase. The gene encoding BAP1 is mutated in various human cancers, including mesothelioma, uveal melanoma and renal cell carcinoma. BAP1 plays roles in many cancer-related cellular functions, including cell proliferation, cell death, and nuclear processes crucial for genome stability, such as DNA repair and replication. While these findings suggest that BAP1 functions as a tumor suppressor, recent data also suggest that BAP1 might play tumor-promoting roles in certain cancers, such as breast cancer and hematopoietic malignancies. Here, we show that BAP1 is upregulated in colon cancer cells and tissues and that BAP1 depletion reduces colon cancer cell proliferation and tumor growth. BAP1 contributes to colon cancer cell proliferation by accelerating DNA replication and suppressing replication stress and concomitant apoptosis. A recently identified BAP1 inhibitor, TG2-179-1, which seems to covalently bind to the active site of BAP1, exhibits potent cytotoxic activity against colon cancer cells, with half-maximal inhibitory concentrations of less than 10 μM, and inhibits colon tumor growth. TG2-179-1 exerts cytotoxic activity by targeting BAP1, leading to defective replication and increased apoptosis. This work therefore shows that BAP1 acts oncogenically in colon cancer and is a potential therapeutic target for this cancer. Our work also suggests that TG2-179-1 can be developed as a potential therapeutic agent for colon cancer.

DNA methylation-based subtypes of acute myeloid leukemia with distinct prognosis and clinical features.

Acute myeloid leukemia (AML) is a malignancy of the stem cell precursors of the myeloid lineage. DNA methylation is an important DNA modification that regulates gene expression. Investigating AML heterogeneity based on DNA methylation could be clinically informative for improving clinical diagnosis and prognosis. The AML subtypes based on DNA methylation were identified by unsupervised consensus clustering. The association of these subtypes with gene mutation, copy number variations, immune infiltration and clinical features were further explored. Finally, univariate, LASSO and multivariate cox regression analyses were used to identify prognosis-associated genes and construct risk model for AML patients. In addition, we validated this model by using other datasets and explored the involved biological functions and pathways of its related genes. Three CpG island methylator phenotypes (CIMP-H, CIMP-M and CIMP-L) were identified using the 91 differential CpG sites. Overall survival, morphology, macrophages M0 and monocytes were distinct from each other. The most frequently mutated gene in CIMP-L was DNMT3A while which in CIMP-M that was RUNX1. In addition, the TIDE scores, used to predict the response to immune checkpoint inhibitors, were significantly different among CIMPs. The CIMP-associated prognosis risk model (CPM) using 32 key genes had convinced accuracy of prediction to forecast 0.5-year, 1-year, 3-year and 5-year survival rates. Moreover, the risk score-related genes were significantly enriched in pattern specification process, regionalization, embryonic organ morphogenesis and other critical cancer-related biological functions. We systematically and comprehensively analyzed the DNA methylation in AML. The risk model we constructed is an independent predictor of overall survival in AML and could be used as prognostic factor for AML treatment.

PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types.

Phosphatase of Regenerating Liver-3 (PRL3) was discovered in 1998 and was subsequently found to be correlated with cancer progression and metastasis in 2001. Extensive research in the past two decades has produced significant findings on PRL3-mediated cancer signaling and functions, as well as its clinical relevance in diverse types of cancer. PRL3 has been established to play a role in many cancer-related functions, including but not limited to metastasis, proliferation, and angiogenesis. Importantly, the tumor-specific expression of PRL3 protein in multiple cancer types has made it an attractive therapeutic target. Much effort has been made in developing PRL3-targeted therapy with small chemical inhibitors against intracellular PRL3, and notably, the development of PRL3-zumab as a novel cancer immunotherapy against PRL3. In this review, we summarize the current understanding of the role of PRL3 in cancer-related cellular functions, its prognostic value, as well as perspectives on PRL3 as a target for unconventional immunotherapy in the clinic with PRL3-zumab.