Bmal1 regulates the stemness and tumorigenesis of gliomas with the Wnt/ß-catenin signaling pathway.

BACKGROUND: The circadian rhythm gene Brain and Muscle Arnt-like1 (Bmal1) acts as a transcription factor and plays a crucial role in oncogenesis and embryonic development. Bmal1 is notably overexpressed in various tumors, including glioma. However, the precise mechanisms underlying the elevated Bmal1 expression in glioma malignancy remain unclear. METHODS: This study employed multiple databases, including The Cancer Genome Atlas (TCGA), GTEx, and cBioportal, to analyze Bmal1 mRNA expression in gliomas, evaluate its prognostic significance, investigate transcriptome alterations, identify key signaling pathways associated with Bmal1, and examine its interaction with tumor stem cells. Additionally, experimental validation was performed to confirm Bmal1's regulatory effects on glioma stem cells. RESULTS: Our analysis revealed differential Bmal1 expression across glioma grades and molecular subtypes. Moreover, Bmal1 significantly influences several tumor-related signaling pathways, notably the Mapk, Met, and Wnt pathways, and is actively involved with stem cells. A strong positive correlation was observed between Bmal1 and glioma stem cell markers, such as Nestin, Sox2, and Cd133. Experimental validation confirmed that Bmal1 promotes stem cell expansion and tumor progression via the Wnt/ß-catenin pathway. CONCLUSION: This study underscores the critical regulatory function of Bmal1 in glioma development. The interaction between Bmal1 and glioma stem cells appears to significantly impact glioma initiation and progression.

Role of Sam68 in different types of cancer (Review).

Src­associated in mitosis 68 kDa protein (Sam68) is a protein encoded by the heteronuclear ribonucleoprotein particle K homology (KH) single domain­containing, RNA­binding, signal transduction­associated protein 1 (known as KHDRBS1) gene in humans. This protein contains binding sites for critical components in a variety of cellular processes, including the regulation of gene expression, RNA processing and cell signaling. Thus, Sam68 may play a role in a variety of diseases, including cancer. Sam68 has been widely demonstrated to participate in tumor cell proliferation, progression and metastasis to be involved in the regulation of cancer stem cell self­renewal. Based on the body of evidence available, Sam68 emerges as a promising target for this disease. The objectives of the present included summarizing the role of Sam68 in cancer murine models and cancer patients, unraveling the molecular mechanisms underlying its oncogenic potential and discussing the effectiveness of antitumor agents in reducing the malignant effects of Sam68 during tumorigenesis.

The relationship between keratin 18 and epithelial-derived tumors: as a diagnostic marker, prognostic marker, and its role in tumorigenesis.

As a structural protein, keratin is mainly expressed in epithelial cells and skin appendages to provide mechanical support and external resistance. The keratin family has a total of 54 members, which are divided into type I and type II. Two types of keratins connect to each other to form keratin intermediate filaments and participate in the construction of the cytoskeleton. K18 is a non-hair keratin, which is widely expressed in simple epithelial tissues with its partner, K8. Compared with mechanical support, K8/K18 pairs play more important roles in biological regulation, such as mediating anti-apoptosis, regulating cell cycle progression, and transmitting signals. Mutations in K18 can cause a variety of non-neoplastic diseases of the visceral epithelium. In addition, the expression levels of K18 are frequently altered in various epithelial-derived tumors, especially adenocarcinomas, which suggests that K18 may be involved in tumorigenesis. Due to the specific expression pattern of K18 in tumor tissues and its serum level reflecting tumor cell death, apply K18 to diagnose tumors and predict its prognosis have the potential to be simple and effective alternative methods. However, these potential roles of K18 in tumors have not been fully summarized. In this review, we focus on the relationship between K18 and epithelial-derived tumors, discuss the value of K18 as a diagnostic and prognostic marker, and summarize the interactions of K18 with various related proteins in tumorigenesis, with examples of simple epithelial tumors such as lung, breast, liver, and gastrointestinal cancers.

GABPA inhibits tumorigenesis in clear cell renal cell carcinoma by regulating ferroptosis through ACSL4.

Clear cell renal cell carcinoma (ccRCC) is a common genitourinary malignancy characterized by dysregulated cellular metabolism leading to aberrant glucose metabolism, fatty acid accumulation, and excessive reactive oxygen species production. ccRCC cells exhibit an augmented oxidative stress response. Complex interactions between iron metabolism and lipid homeostasis in ccRCC cells require a counteracting response that enables ferroptosis evasion and survival maintenance. Additionally, abnormal GA-binding protein transcription factor subunit alpha (GABPA) expression is associated with ccRCC occurrence and development, but its impact on ferroptosis-related molecular mechanisms remains unclear. Herein, we examined the impact of the GABPA-ACSL4 pathway on ferroptosis in ccRCC through bioinformatics analysis, as well as in vitro and in vivo experiments. In contrast to that in adjacent normal tissues, GABPA expression was significantly downregulated in ccRCC tissues, and this downregulation was linked to poor overall survival. Increased GABPA expression suppressed ccRCC cell proliferation, migration, and invasion. Moreover, GABPA overexpression increased the susceptibility of ccRCC cells to ferroptosis. Additionally, GABPA directly bound to the promoter region of ACSL4, promoting ferroptosis. Thus, inducing the GABPA-ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development.

The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity.

Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.

Induction of interleukin-6 by SPZ1-mediated Wnt5a signaling boosts progression of nasopharyngeal carcinoma cells.

Nasopharyngeal carcinoma (NPC) is a common malignancy in Southeast Asia, and in the Guangxi and Guangdong provinces of China. The spermatogenic transcription factor zip 1 (SPZ1) is a member of bHLH zip family, and promotes tumorigenesis in the liver, colon and breast tissues. However, the role of SPZ1 in the progression of NPC is unclear. In this study, we found that SPZ1 mRNA and protein levels were significantly upregulated in NPC tissues compared to the normal nasopharyngeal tissues. Furthermore, SPZ1 knockdown in NPC cell lines inhibited proliferation, epithelial-mesenchymal transition, migration, and invasion in vitro, and suppressed tumorigenesis in an in vivo model. On the other hand, SPZ1 overexpression facilitated the growth of NPC cells. Mechanistically, SPZ1-driven progression of NPC is dependent on the Wnt5a/interleukin-6 (IL-6) signaling pathway. Consistent with this, IL-6 levels were significantly increased in NPC tissues and correlated positively with SPZ1 expression. Taken together, our findings suggest that SPZ1 mediates NPC progression through Wnt5a/IL-6 signaling, and the SPZ1/Wnt5a/IL-6 axis is a potential therapeutic target for NPC.

miRNA-21, an oncomiR that regulates cell proliferation, migration, invasion and therapy response in lung cancer.

Lung cancer is the leading cause of cancer-related death globally, with poor survival rates due mostly to a lack of early detection. The usual diagnostic technique includes a biopsy, which is frequently performed later in the disease's progression. In order to uncover processes that improve illness detection and prognosis, miRNA-21 emerges as a major miRNA identified in a variety of cancer types, including lung cancer. This review compiles insights into the involvement of miRNA-21 within the distinct cellular processes underlying lung cancer. To achieve this, we conducted an extensive literature review, drawing from published in vitro, in vivo and clinical trials studies. Searches were performed in the PubMed, Scielo, CAPES Journal Portal, BVS, INCA, and Clinical Trials.Gov. Only English written articles were selected. As screening criteria, we selected articles that explored the modulation pathways of miRNA-21, along with the proteins and genes implicated in tumorigenesis, metastasis, therapy resistance to established treatments, and their significance in the diagnosis and prognosis of lung cancer. A total of 3294 articles were identified, and 37 papers were selected to compose the review, after analysing selection criteria. Of these, 57 % studies presented in vitro evaluation, 22 % studies showed in vivo analysis, and 12 clinical trials were found. This study elucidates the principal signaling pathways influenced by miRNA-21, which play a pivotal role in lung cancer development. This comprehensive review sheds light on the potential significance of miRNA-21 as a critical mechanism for improving the prognosis of lung cancer patients, facilitating the transition of experimental data into the clinical phase. Therefore, we summarized published articles of miRNA-21 modulated signal pathways in lung cancer.

Alternative splicing in ovarian cancer.

Ovarian cancer is the second leading cause of gynecologic cancer death worldwide, with only 20% of cases detected early due to its elusive nature, limiting successful treatment. Most deaths occur from the disease progressing to advanced stages. Despite advances in chemo- and immunotherapy, the 5-year survival remains below 50% due to high recurrence and chemoresistance. Therefore, leveraging new research perspectives to understand molecular signatures and identify novel therapeutic targets is crucial for improving the clinical outcomes of ovarian cancer. Alternative splicing, a fundamental mechanism of post-transcriptional gene regulation, significantly contributes to heightened genomic complexity and protein diversity. Increased awareness has emerged about the multifaceted roles of alternative splicing in ovarian cancer, including cell proliferation, metastasis, apoptosis, immune evasion, and chemoresistance. We begin with an overview of altered splicing machinery, highlighting increased expression of spliceosome components and associated splicing factors like BUD31, SF3B4, and CTNNBL1, and their relationships to ovarian cancer. Next, we summarize the impact of specific variants of CD44, ECM1, and KAI1 on tumorigenesis and drug resistance through diverse mechanisms. Recent genomic and bioinformatics advances have enhanced our understanding. By incorporating data from The Cancer Genome Atlas RNA-seq, along with clinical information, a series of prognostic models have been developed, which provided deeper insights into how the splicing influences prognosis, overall survival, the immune microenvironment, and drug sensitivity and resistance in ovarian cancer patients. Notably, novel splicing events, such as PIGV|1299|AP and FLT3LG|50,941|AP, have been identified in multiple prognostic models and are associated with poorer and improved prognosis, respectively. These novel splicing variants warrant further functional characterization to unlock the underlying molecular mechanisms. Additionally, experimental evidence has underscored the potential therapeutic utility of targeting alternative splicing events, exemplified by the observation that knockdown of splicing factor BUD31 or antisense oligonucleotide-induced BCL2L12 exon skipping promotes apoptosis of ovarian cancer cells. In clinical settings, bevacizumab, a humanized monoclonal antibody that specifically targets the VEGF-A isoform, has demonstrated beneficial effects in the treatment of patients with advanced epithelial ovarian cancer. In conclusion, this review constitutes the first comprehensive and detailed exposition of the intricate interplay between alternative splicing and ovarian cancer, underscoring the significance of alternative splicing events as pivotal determinants in cancer biology and as promising avenues for future diagnostic and therapeutic intervention.

Chronic exposure to hexavalent chromium induces esophageal tumorigenesis via activating the Notch signaling pathway. / å ­ä»·é“¬çš„æ ¢æ€§æš´éœ²å¯é€šè¿‡æ¿€æ´»Notch信号通路诱导食管肿瘤发生.

Hexavalent chromium Cr(VI), as a well-established carcinogen, contributes to tumorigenesis for many human cancers, especially respiratory and digestive tumors. However, the potential function and relevant mechanism of Cr(VI) on the initiation of esophageal carcinogenesis are largely unknown. Here, immortalized human esophageal epithelial cells (HEECs) were induced to be malignantly transformed cells, termed HEEC-Cr(VI) cells, via chronic exposure to Cr(VI), which simulates the progress of esophageal tumorigenesis. In vitro and in vivo experiments demonstrated that HEEC-Cr(VI) cells obtain the ability of anchorage-independent growth, greater proliferative capacity, cancer stem cell properties, and the capacity to form subcutaneous xenografts in BALB/c nude mice when compared to their parental cells, HEECs. Additionally, HEEC-Cr(VI) cells exhibited weakened cell motility and enhanced cell adhesion. Interestingly, HEECs with acute exposure to Cr(VI) failed to display those malignant phenotypes of HEEC-Cr(VI) cells, suggesting that Cr(VI)|-induced malignant transformation, but not Cr(VI) itself, is the cause for the tumor characteristics of HEEC-Cr(VI) cells. Mechanistically, chronic exposure to Cr(VI) induced abnormal activation of Notch signaling, which is crucial to maintaining the capacity for malignant proliferation and stemness of HEEC-Cr(VI) cells. As expected, N-|[N-|(3,5-difluorophenacetyl)|-L-alanyl]|-S-phenylglycine t-butyl ester (DAPT), an inhibitor for the Notch pathway, drastically attenuated cancerous phenotypes of HEEC-Cr(VI) cells. In conclusion, our study clarified the molecular mechanism underlying Cr(VI)|-induced esophageal tumorigenesis, which provides novel insights for further basic research and clinical therapeutic strategies about Cr(VI)|-associated esophageal cancer.

Kallikrein-related peptidases: mechanistic understanding for potential therapeutic targeting in cancer.

INTRODUCTION: Human kallikrein-related peptidases (KLKs) represent a subgroup of 15 serine endopeptidases involved in various physiological processes and pathologies, including cancer. AREAS COVERED: This review aims to provide a comprehensive overview of the KLK family, highlighting their genomic structure, expression profiles and substrate specificity. We explore the role of KLKs in tumorigenesis, emphasizing their potential as biomarkers and therapeutic targets in cancer treatment. The dysregulated activity of KLKs has been linked to various malignancies, making them promising candidates for cancer diagnostics and therapy. EXPERT OPINION: : Recent advancements in understanding the mechanistic pathways of KLK-related tumorigenesis offer new prospects for developing targeted cancer treatments. Expert opinion suggests that while significant progress has been made, further research is necessary to fully exploit KLKs' potential in clinical applications.

From pathogenesis to treatment: the impact of bacteria on cancer.

The intricate relationship between cancer and bacteria has garnered increasing attention in recent years. While traditional cancer research has primarily focused on tumor cells and genetic mutations, emerging evidence highlights the significant role of microbial communities within the tumor microenvironment in cancer development and progression. This review aims to provide a comprehensive overview of the current understanding of the complex interplay between cancer and bacteria. We explore the diverse ways in which bacteria influence tumorigenesis and tumor behavior, discussing direct interactions between bacteria and tumor cells, their impact on tumor immunity, and the potential modulation of the tumor microenvironment. Additionally, we delve into the mechanisms through which bacterial metabolites and extracellular products May affect cancer pathways. By conducting a thorough analysis of the existing literature, we underscore the multifaceted and intricate relationship between bacteria and cancer. Understanding this complex interplay could pave the way for novel therapeutic approaches and preventive strategies in cancer treatment.

Midkine as a driver of age-related changes and increase in mammary tumorigenesis.

Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.

Virtual screening, molecular dynamics simulations, and in vitro validation of EGFR inhibitors as breast cancer therapeutics.

A high abundance of Epidermal Growth Factor Receptor (EGFR) in malignant cells makes them a prospective therapeutic target for basal breast tumors. Although EGFR inhibitors are in development as anticancer therapeutics, there exists limitations due to the dose-limiting cytotoxicity that limits their clinical utilization, thereby necessitating the advancement of effective inhibitors. In the present study, we have developed common pharmacophore hypotheses using 30 known EGFR inhibitors. The best pharmacophore hypothesis DHRRR_1 was utilized for virtual screening (VS) of the Phase database containing 4.3 × 106 fully prepared compounds. The top 1000 hits were further subjected to ADME filtration followed by structure-based VS and Molecular Dynamics (MD) simulation investigations. Based on pharmacophore hypothesis matching, XP glide score, interactions between ligands and active site residues, ADME properties, and MD simulations, the five best hits (SN-01 through SN-05) were preferred for in-vitro cytotoxicity studies. All the molecules except SN-02 exhibited cytotoxicity in Triple Negative Breast Cancer (TNBC) cells. These potential EGFR inhibitors effectively downregulated the EGF-induced proliferation, migration, in-vitro tumorigenic capability, and EGFR activation (pEGFR) in the TNBCs. Additionally, in combination with doxorubicin, the identified EGFR inhibitors significantly decreased the EGF-induced proliferation. SN-04, and SN-05 in the presence of a lower concentration of doxorubicin markedly increased the apoptotic markers expression in the TNBCs, an effect which was comparable to a higher concentration of doxorubicin treatment, alone. These observations suggest that both SN-04 and/or SN-05 can improve the efficacy of chemotherapeutic drug, doxorubicin at a lower concentration to avert the higher dose of chemotherapeutic-induced side effects during breast cancer treatment.

Delta-Like Homolog 2 Facilitates Malignancy of Hepatocellular Carcinoma via Activating EGFR/PKM2 Signaling Pathway.

Delta-like homolog 2 (DLK2) plays a crucial role in adipogenesis, chondrogenic differentiation, and the progression of certain cancers. However, the key roles of DLK2 underlying the progression of hepatocellular carcinoma (HCC) remain ambiguous. In the current study, we demonstrate that DLK2 is upregulated in HCC, significantly correlated with clinicopathological variables and serves as an independent diagnostic marker. Functional assays reveal that DLK2 facilitates malignant progression of HCC in vitro and in vivo models. Mechanistically, DLK2 binds to EGFR resulting in its auto-phosphorylation, which activates NK-κB pathway leading to P65-dependent transcriptional upregulation of PKM2. Furthermore, that elevates both enzyme-dependent and -independent activities of PKM2 contributing to cancer proliferation and metastasis. In summary, our findings demonstrate a novel pro-tumoral role and mechanism of DLK2 in the regulation of HCC malignant progression, suggesting its potential as a clinical diagnostic marker and therapeutic target.

Long Non-Coding RNA CRNDE, LINC00957, and AC072061.1 as a Promising Diagnostic and Prognostic Biomarker in Glioblastoma Multiforme.

Background: Glioblastoma multiforme (GBM) is one of the most invasive types of brain cancer. LncRNAs can be considered a new prognostic and diagnostic biomarker in GBM. This study comprehensively explored the interaction of lncRNAs with mRNAs in the TCGA database and proposed a novel promising biomarker with favorable diagnostic and prognostic values. Methods: The public data of RNA-seq and related clinical data were downloaded from the TCGA database. Differential expression analysis was conducted in R. GO and KEGG signaling pathways were used for enrichment. The STRING database was used for PPI analysis. CE-network was constructed by STAR database. Kaplan-Meier survival analysis and ROC curve analysis to indicate the biomarkers' diagnostic and prognostic values. Results: Differentially expressed data illustrated that 4428 mRNAs were differentially expressed in GBM. The GO and KEGG pathway analysis showed that the differentially expressed mRNAs were enriched in critical biological processes. The PPI showed that WEE1, BARD1, and CDK6 were the important PPI hubs. The ceRNA network data demonstrated critical lncRNAs. The data revealed that the lncRNA CRNDE, LINC00957, AC072061.1, AC068888.1, and DBH-AS1 are potential diagnostic prognostic biomarkers in the GBM patients. Conclusion: Altogether, we demonstrated lncRNA, and mRNA interaction and mentioned regulatory networks, considered a therapeutic option in GBM. In addition, we proposed potential diagnostic and prognostic biomarkers for the patients.

Application of imaging technology for the diagnosis of malignancy in the pancreaticobiliary duodenal junction (Review).

The pancreaticobiliary duodenal junction (PBDJ) is the connecting area of the pancreatic duct, bile duct and duodenum. In a broad sense, it refers to a region formed by the head of the pancreas, the pancreatic segment of the common bile duct and the intraduodenal segment, the descending and the horizontal part of the duodenum, and the soft tissue around the pancreatic head. In a narrow sense, it refers to the anatomical Vater ampulla. Due to its complex and variable anatomical features, and the diversity of pathological changes, it is challenging to make an early diagnosis of malignancy at the PBDJ and define the histological type. The unique anatomical structure of this area may be the basis for the occurrence of malignant tumors. Therefore, understanding and subclassifying the anatomical configuration of the PBDJ is of great significance for the prevention and treatment of malignant tumors at their source. The present review comprehensively discusses commonly used imaging techniques and other new technologies for diagnosing malignancy at the PBDJ, offering evidence for physicians and patients to select appropriate examination methods.

Non-metabolic enzyme function of pyruvate kinase M2 in breast cancer.

Breast cancer (BC) is a prevalent malignant tumor in women, and its incidence has been steadily increasing in recent years. Compared with other types of cancer, it has the highest mortality and morbidity rates in women. So, it is crucial to investigate the underlying mechanisms of BC development and identify specific therapeutic targets. Pyruvate kinase M2 (PKM2), an important metabolic enzyme in glycolysis, has been found to be highly expressed in BC. It can also move to the nucleus and interact with various transcription factors and proteins, including hypoxia-inducible factor-1α (HIF-1α), signal transducer and activator of transcription 3 (STAT3), ß-catenin, cellular-myelocytomatosis oncogene (c-Myc), nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and mammalian sterile 20-like kinase 1 (MST1). This interaction leads to non-metabolic functions that control the cell cycle, proliferation, apoptosis, migration, invasion, angiogenesis, and tumor microenvironment in BC. This review provides an overview of the latest advancements in understanding the interactions between PKM2 and different transcription factors and proteins that influence the initiation and progression of BC. It also examined how natural drugs and noncoding RNAs affect various biological processes in BC cells through the regulation of the non-metabolic enzyme functions of PKM2. The findings provide valuable insights for improving the prognosis and developing targeted therapies for BC in the coming years.

USP10 promotes cell proliferation, migration, and invasion in NSCLC through deubiquitination and stabilization of EIF4G1.

Lung cancer is one of the most common types of malignant cancer worldwide, causing a serious social and economic burden. It is classified into non-small cell lung cancer (NSCLC) and small cell lung cancer, with NSCLC accounting for 80-85% of cases. Eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) is highly expressed in NSCLC, playing an important role in regulating tumor growth, angiogenesis, malignant transformation, and phagocytosis. Ubiquitin-specific protease 10 (USP10) functions as a deubiquitinating enzyme to regulate substrate protein deubiquitination and reverse the ubiquitin proteasome degradation pathway. Our previous study identified an interaction between EIF4G1 and USP10; however, their regulatory mechanism remains unclear. Herein, we found that USP10 positively regulates EIF4G1 in NSCLC cells. An in vivo ubiquitination assay demonstrated deubiquitination of EIF4G1 by USP10, which reversed the ubiquitin proteasomal degradation of EIF4G1, thereby increasing its stability. Upregulation of EIF4G1 promoted cell proliferation, migration, and invasion in NSCLC cells. The current study not only reveals a novel mechanism through which USP10 positively regulates EIF4G1 in NSCLC, but also demonstrates the potential of USP10 as a therapeutic target to treat NSCLC.

ZIP4: a promising early diagnostic and therapeutic targets for pancreatic cancer.

Pancreatic cancer is an aggressive and metastatic tumor that lacks effective early detection and treatment methods. There is an urgent need to further understand its underlying molecular mechanisms and identify new biomarkers for early detection. Zinc, a critical trace element and catalytic cofactor, is tightly regulated within cells. ZIP4, a zinc transporter protein significantly overexpressed in human pancreatic cancer, appears to play a pivotal role in tumor development by modulating intracellular zinc concentration. This review highlights the role of ZIP4 in tumorigenesis, including its impact on pancreatic cancer growth, proliferation, migration, and drug resistance. ZIP4 exerts its effects by regulating zinc dependent transcriptional factors like CREB, STAT3, and ZEB1, resulting in upregulation of Cyclin D1, TP53INP1, ITGA3, CD44, ENT1 proteins, and miR-373. Moreover, ZIP4 mediates the miR373-PHLPP2-AKT signaling axis, which increases TGF-ß expression. Coupled with CREB-activated macrophage catabolism-related genes SDC1 and DNM2, ZIP4 promotes cancer cachexia and supports amino acids to tumor cells under metabolic stress. Furthermore, ZIP4 facilitates bone resorption by osteoclasts via the RANKL-activated NF-κB pathway. A deeper understanding of these mechanisms may unveil potential targets for early diagnosis, prognosis assessment, and dietary recommendations for pancreatic cancer. These findings hold clinical significance not only for pancreatic cancer but also for other malignancies exhibiting heightened ZIP4 expression.

Advanced imaging reveals enhanced malignancy in glioblastomas involving the subventricular zone: evidence of increased infiltrative growth and perfusion.

BACKGROUND: Glioblastoma's infiltrative growth and heterogeneity are influenced by neural, molecular, genetic, and immunological factors, with the precise origin of these tumors remaining elusive. Neurogenic zones might serve as the tumor stem cells' nest, with tumors in contact with these zones exhibiting worse outcomes and more aggressive growth patterns. This study aimed to determine if these characteristics are reflected in advanced imaging, specifically diffusion and perfusion data. METHODS: In this monocentric retrospective study, 137 glioblastoma therapy-naive patients (IDH-wildtype, grade 4) with advanced preoperative MRI, including perfusion and diffusion imaging, were analyzed. Tumors and neurogenic zones were automatically segmented. Advanced imaging metrics, including cerebral blood volume (CBV) from perfusion imaging, tissue volume mask (TVM), and free water corrected fractional anisotropy (FA-FWE) from diffusion imaging, were extracted. RESULTS: SVZ infiltration positively correlated with CBV, indicating higher perfusion in tumors. Significant CBV differences were noted between high and low SVZ infiltration cases at specific percentiles. Negative correlation was observed with TVM and positive correlation with FA-FWE, suggesting more infiltrative tumor growth. Significant differences in TVM and FA-FWE values were found between high and low SVZ infiltration cases. DISCUSSION: Glioblastomas with SVZ infiltration exhibit distinct imaging characteristics, including higher perfusion and lower cell density per voxel, indicating a more infiltrative growth and higher vascularization. Stem cell-like characteristics in SVZ-infiltrating cells could explain the increased infiltration and aggressive behavior. Understanding these imaging and biological correlations could enhance the understanding of glioblastoma evolution.