Therapeutic Target For Malignancy Research Articles

Lymphocyte homing and recirculation with tumor tertiary lymphoid structure formation: predictions for successful cancer immunotherapy.

The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies.

Abstract A010: Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis

Abstract In the intrinsic pathway of apoptosis, death stimuli (including drugs, cellular stress, viral infections, etc.) trigger the oligomerization of BAX and BAK resulting in pore formation in the outer mitochondrial membrane to release cytochrome c from the intermembrane space. The released cytochrome c then activates APAF-1 and CASPASE9 to form a 1.4 MDa complex known as apoptosome, which recruits and activates downstream caspases that dismantle the cell. However, we have found that proteasome inhibition leads to a BAX and BAK independent apoptotic cell death. We show using immunofluorescence, fluorogenic assays, and flow cytometry that the proteasome inhibitors, bortezomib and MG-132, trigger a caspase dependent cell death that requires the apoptosome components APAF-1 and CASPASE9, but not cytochrome c. Furthermore, size exclusion chromatography revealed that unlike classical death stimuli, which induce the mega-dalton canonical apoptosome fomation, proteasome inhibitors induce a minor shift in APAF-1, forming a smaller, non-canonical apoptosome. Current efforts are focused on the identification of the APAF-1 activator. Our results indicate the existence of a non-canonical caspase-dependent cell death pathway, which could be a novel therapeutic target in malignancies by bypassing the BCL-2 family of apoptotic regulators. Citation Format: Tresor O Mukiza, Ricardo Enrique-Rodriguez, Amit Budhraja, Lauren Brakefield, Tudor Moldoveanu, Joseph T Opferman. Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A010.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets

BackgroundThe major facilitator superfamily glucose transporters (GLUTs), encoded by solute carrier 2A (SLC2A) genes, mediate the transmembrane movement and uptake of glucose. To satisfy the improved energy demands, glycolysis flux is increased in cancers compared with healthy tissues. Multiple diseases, including cancer, have been associated with GLUTs. Nevertheless, not much research has been done on the functions of SLC2As in pan-cancer prognosis or their clinical treatment potential. MethodsThe SLC2A family genes' level of expression and prognostic values were analyzed in relation to pan-cancer. We then examined the association among SLC2As expression and TME, Stemness score, clinical characteristics, immune subtypes, and drug sensitivity. We merged bioinformatics analysis techniques with up-to-date public databases. Additionally, SLC2As from the KOBAS database were subjected to enrichment analysis. ResultsWe discovered that SLC2As' gene expression differed significantly between normal tissues and many malignancies. A number of tumors from various databases demonstrate a relationship between prognosis and SLC2A family gene expression. For instance, SLC2A2 and SLC2A5 were associated with the overall survival (OS) of hepatocellular carcinoma. SLC2A1 was associated with the OS of lung adenocarcinoma and pancreatic adenocarcinoma. Moreover, the SLC2A family gene expression is significantly correlated with the pan-cancer stromal and immune scores, and the RNA and DNA stemness scores. Furthermore, we found that the majority of SLC2As had a strong correlation with the tumor stages in KIRC. The immunological subtypes and all members of the SLC2A gene family exhibited a substantial correlation. Moreover, pathways containing insulin resistance and adipocytokine signaling pathway may influence the progression of some cancers. Finally, there is a significant positive or negative connection between drug sensitivity and SLC2A1 expression. ConclusionOur research highlights the significant promise of SLC2As as prognostic indicators and offers insightful approaches for upcoming exploration of SLC2As as putative therapeutic targets in malignancies.

The Impact of Trophoblast Cell-Surface Antigen 2 Expression on the Survival of Patients with Gastrointestinal Tumors: A Systematic Review.

Trophoblast cell-surface antigen 2 (TROP-2) is a transmembrane glycoprotein expressed in epithelial cells that has been associated with malignant progression in most carcinomas. Accordingly, the genetic complexity of gastrointestinal tumors necessitates the investigation of new biomarkers with potential prognostic value. The aim of this systematic review is to assess the effect of TROP-2 on the overall survival of patients who underwent surgery for gastrointestinal malignancy. The present systematic review was designed using the PRISMA and AMSTAR guidelines. We searched the Pubmed, EMBASE and CENTRAL databases from their inception to September 2023. Ten studies that enrolled 2293 patients were included for qualitative analysis. Six studies evaluated patients with colorectal cancer, two studies included patients with gastric carcinoma, patients with pancreatic cancer were included in one study and one study included hepatobiliary cancer patients. TROP-2 was positive in 1005/2293 samples of the immunohistochemically evaluated biopsies and was associated with poor overall survival in all studies. High intensity was also associated with more aggressive histopathological characteristics, such us deep tissue invasion, lymph node metastasis and cell atypia. The prognostic value of TROP-2 was shown to be enhanced in patients with advanced disease and poor histological differentiation. TROP-2 was expressed at high levels in gastrointestinal tumors, which was associated with both tumor development and pathological aggressiveness. Therefore, TROP-2 could be used as a biomarker to determine clinical prognosis and as a potential therapeutic target in malignancies of the gastrointestinal tract, but further studies need to validate it.

REDH: A database of RNA editome in hematopoietic differentiation and malignancy.

The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. REDH is accessible at http://www.redhdatabase.com/ . This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in ap53-dependent manner.

Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.

The association and clinical relevance of phase-separating protein CAPRIN1 with noncoding RNA.

CAPRIN1, cell cycle-associated protein 1, is an RNA-binding protein in stress granules, P bodies, and messenger RNA transport granules and has a high level of expression in cancer. It promotes the proliferation and invasion of cancer cells and enhances their glycolysis and chemoresistance. In addition, it mediates the formation of intracellular SGs in various ways when exposed to endogenousandexogenousstress. As an RNA-binding protein, it not only directly binds to several mRNAs associated with the cell cycle but also is the target of miRNA, lncRNA, and circRNA. Recently, CAPRIN1 is identified as a phase-separating protein that mediates the liquid-liquid phase separation within tumor cells. Moreover, the formation of CAPRIN1-mediated phase separation is regulated by circRNA and lncRNA. In addition, CAPRIN1 is associated with ubiquitination, which affects the relevant characteristics of cancer cells. This review discusses the different regulatory mechanisms of CAPRIN1 in various tumors and its association with noncoding RNA, suggesting its potential as an oncogenic signal and possibly as a diagnostic indicator in the future. This may provide the multifunctional characteristic insight of CAPRIN1 protein and potential therapeutic target in malignancy with high levels of CAPRIN1.

Loss of Dok-3 in Non-tumor Cells Induces Malignant Transformation of Benign Epithelial Tumor Cells of the Intestine.

This study uncovers tumor cell-extrinsic cues that can induce malignant conversion of benign tumors without intensifying mutagenesis in tumors, a novel concept potentially providing a new therapeutic target in malignancy.

The Emerging Role of PIWI-Interacting RNAs (piRNAs) in Gastrointestinal Cancers: An Updated Perspective.

Simple SummaryGastrointestinal (GI) cancers are high mortality malignancies due to late diagnosis, the presence of metastasis and drug resistance development. Novel and more reliable biomarkers and therapeutic targets are still needed for these diseases. PIWI-interacting RNAs (piRNAs) are small transcripts that are involve in gastrointestinal carcinogenesis and have been proposed as promising diagnostic or prognostic biomarkers and as potential therapeutic targets in these malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers. In addition, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers.Gastrointestinal (GI) cancers produce ~3.4 million related deaths worldwide, comprising 35% of all cancer-related deaths. The high mortality among GI cancers is due to late diagnosis, the presence of metastasis and drug resistance development. Additionally, current clinical markers do not adequately guide patient management, thereby new and more reliable biomarkers and therapeutic targets are still needed for these diseases. RNA-seq technology has allowed the discovery of new types of RNA transcripts including PIWI-interacting RNAs (piRNAs), which have particular characteristics that enable these molecules to act via diverse molecular mechanisms for regulating gene expression. Cumulative evidence has described the potential role of piRNAs in the development of several tumor types as a likely explanation for certain genomic abnormalities and signaling pathways’ deregulations observed in cancer. In addition, these piRNAs might be also proposed as promising diagnostic or prognostic biomarkers or as potential therapeutic targets in malignancies. This review describes important topics about piRNAs including their molecular characteristics, biosynthesis processes, gene expression silencing mechanisms, and the manner in which these transcripts have been studied in samples and cell lines of GI cancers to elucidate their implications in these diseases. Moreover, this article discusses the potential clinical usefulness of piRNAs as biomarkers and therapeutic targets in GI cancers.

LncRNA LINC00460: Function and mechanism in human cancer.

Long non‐coding RNAs (LncRNAs), which are more than 200 nucleotides in length and with limited protein‐coding potential, play vital roles in the pathogenesis, tumorigenesis, and angiogenesis of cancers. Aberrant expression of lncRNAs has been detected in various carcinomas and may be correlated with oncogenesis by affecting related genes expression. Recently, an increasing number of studies have reported on long intergenic non‐protein coding RNA 460 (LINC00460) in human tumor fields. LINC00460 is upregulated in diverse cancer tissues and cells. The upregulated expression level of LINC00460 is correlated with larger tumor size, tumor node metastasis (TNM) stage, lymph node metastasis, and shorter overall survival. The regulatory mechanism of LINC00460 was complex and diverse. LINC00460 could act as a competitive endogenous RNA (ceRNA), directly bind with proteins or regulate multiple pathways, which affected tumor progression. Moreover, LINC00460 was also identified to increase drug resistance, and therefore, weaken the effectiveness of tumor treatment. It has become increasingly important to investigate the roles of LINC00460 in various cancers by different mechanisms. Therefore, a more comprehensive understanding of LINC00460 is crucial to expound on the cellular function and molecular mechanism of human cancers. In this review, we refer to studies concerning LINC00460 and provide the basis for the evaluation of LINC00460 as a predicted biomarker or potential therapeutic target in malignancies, and also provide ideas for the future research of lncRNAs similar to LINC00460.

Long Non-coding RNA Small Nucleolar RNA Host Gene 14, a Promising Biomarker and Therapeutic Target in Malignancy.

Small nucleolar RNA host gene 14 (SNHG14) is a long non-coding RNA found to be overexpressed in various types of cancers. Moreover, the expression level of SNHG14 was closely associated with multiple clinicopathological characteristics such as prognosis, tumor differentiation, TNM stage, and lymph node metastasis. Functionally, gain- and loss-of-function of SNHG14 revealed that overexpressed SNHG14 promoted cancer cell viability, invasion, and migration, whereas its down-regulation produced the opposite effect. Mechanistically, regulating its target gene expression by sponging distinct miRNAs might be the major mechanism underlying the oncogenic functions of SNHG14. Thus, SNHG14 might be a promising prognostic biomarker and therapeutic target for cancers. In this review, we discuss the expression profile, biological function, and molecular mechanisms of SNHG14 in cancers to provide a molecular basis for the clinical utility of SNHG14 in the future.

PIM Kinases in Multiple Myeloma.

Simple SummaryMultiple myeloma is the second most common hematologic malignancy in the United States. Eventually, all myeloma patients will relapse and develop resistance to currently available agents. There is an unmet medical need to identify novel therapeutic targets. PIM kinases play an important role in myeloma pathogenesis and disease relapse. We herein provided a comprehensive review on the roles of PIM kinases in myeloma cell survival and proliferation and in the bone marrow microenvironment that supports myeloma growth. The development and testing of novel PIM kinase inhibitors were summarized. Finally, the preclinical studies of the combinatorial effects of PIM kinase inhibitors and other anti-myeloma agents were presented.Multiple myeloma (MM) remains an incurable disease and novel therapeutic agents/approaches are urgently needed. The PIM (Proviral insertion in murine malignancies) serine/threonine kinases have 3 isoforms: PIM1, PIM2, and PIM3. PIM kinases are engaged with an expansive scope of biological activities including cell growth, apoptosis, drug resistance, and immune response. An assortment of molecules and pathways that are critical to myeloma tumorigenesis has been recognized as the downstream targets of PIM kinases. The inhibition of PIM kinases has become an emerging scientific interest for the treatment of multiple myeloma and several PIM kinase inhibitors, such as SGI-1776, AZD1208, and PIM447 (formerly LGH447), have been developed and are under different phases of clinical trials. Current research has been focused on the development of a new generation of potent PIM kinase inhibitors with appropriate pharmacological profiles reasonable for human malignancy treatment. Combination therapy of PIM kinase inhibitors with chemotherapeutic appears to create an additive cytotoxic impact in cancer cells. Notwithstanding, the mechanisms by which PIM kinases modulate the immune microenvironment and synergize with the immunomodulatory agents such as lenalidomide have not been deliberately depicted. This review provides a comprehensive overview of the PIM kinase pathways and the current research status of the development of PIM kinase inhibitors for the treatment of MM. Additionally, the combinatorial effects of the PIM kinase inhibitors with other targeted agents and the promising strategies to exploit PIM as a therapeutic target in malignancy are highlighted.

Clinicopathological and prognostic significance of LINC00673 in human malignancy: a review and meta-analysis.

Background: We conducted this research to investigate the relationship between long intergenic non-protein coding RNA 673 (linc00673) expression and prognosis and clinicopathological parameters in human malignancies.Methods: The PubMed, Embase, WOS, and CNKI databases were used to collect eligible research data before 4 January 2021. Meta-analysis was performed using Stata 12.0 software. Pooled odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence interval (CIs) were calculated to evaluate the association of linc00673 expression with survival outcomes and clinical parameters.Results: We finally included 17 articles and a total of 1539 cases for the meta-analysis. The results indicated that linc00673 was significantly correlated with T stage (P=0.006), tumor stage (P<0.001), lymph node metastasis (P<0.001), and distant metastasis (P<0.001). In addition, the results suggested that elevated linc00673 expression predicted a poor overall survival (OS) time (P=0.013) and acted as an independent prognostic factor (P<0.001) for OS in patients with malignancy. Although potential evidence of publication bias was found in the studies on OS in relation to tumor stage in the multivariate analysis, the trim-and-fill analysis confirmed that the results remained stable.Conclusions: Overexpression of linc00673 was significantly correlated with shorter OS time in patients with malignant tumors. Moreover, the increased expression level of linc00673 was significantly correlated with T stage, tumor stage, lymph node metastasis, and distant metastasis. The results presented in this article revealed that linc00673 might be involved in the progression and invasion of malignancy and serve as a novel prognostic biomarker and potential therapeutic target for malignancy.

Delta-like canonical Notch ligand 3 as a potential therapeutic target in malignancies: A brief overview.

Delta‐like canonical Notch ligand 3 (DLL3) is a member of the Delta/Serrate/Lag2 (DSL) Notch receptor ligand family and plays a crucial role in Notch signaling, which influences various cellular processes including differentiation, proliferation, survival, and apoptosis. DLL3 is expressed throughout the presomitic mesoderm and is localized to the rostral somatic compartments; mutations in DLL3 induce skeletal abnormalities such as spondylocostal dysostosis. Recently, DLL3 has attracted interest as a novel molecular target due to its high expression in neuroendocrine carcinoma of the lung. Moreover, a DLL3‐targeting Ab‐drug conjugate, rovalpituzumab tesirine (ROVA‐T), has been developed as a new treatment with proven antitumor activity. However, the development of ROVA‐T was suspended because of shorter overall survival compared to topotecan, the second‐line standard treatment. Thus, several studies on the mechanism and function of DLL3 in several malignancies are underway to find a new strategy for targeting DLL3. In this review, we discuss the roles of DLL3 in various malignancies and the future perspectives of DLL3‐related research, especially as a therapeutic target.

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target.

During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.

Promising role of long non-coding RNA PCAT6 in malignancies

Long non-coding RNAs (lncRNAs), a newly identified class of non-coding RNA (ncRNA), are defined as RNA molecules at least 200 nucleotides in length that are not translated into proteins. LncRNAs contribute to a wide range of biological processes and are master regulators of disease occurrence, development, and response to therapy in human malignancies. The lncRNA prostate cancer‑associated transcript 6 (PCAT6) is upregulated in various human malignancies, including lung cancer, hepatocellular carcinoma, cervical cancer, osteosarcoma, glioblastoma, colorectal cancer, breast cancer, gastric cancer, gastrointestinal stromal tumors, and pancreatic ductal adenocarcinoma. High expression of PCAT6 is closely correlated with aggressive clinicopathological characteristics and poor prognosis in cancer patients, suggesting it is an oncogenic lncRNA. PCAT6 overexpression also facilitates cell proliferation, invasion, and migration while attenuating apoptosis, indicating that it might serve as a new prognostic biomarker and therapeutic target for malignancies. Here, we discuss the molecular mechanisms, regulatory functions, and potential clinical applications of PCAT6 in cancer.

Inhibition of glycolytic activator PFKFB3 suppresses tumor growth and induces tumor vessel normalization in hepatocellular carcinoma.

Glycolysis emerges as a new therapeutic target for malignancies. The inhibition of glycolytic activator, PFKFB3, repairs tumor endothelial cell function, and normalizing the tumor microenvironment. We aimed to investigate the significance of PFKFB3 in HCC, and the effects of the PFKFB3 inhibitor, PFK15, in HCC tumor cells and tumor endothelial cells. Double immunofluorescent staining of PFKFB3 and CD31 in HCC tissues revealed that high PFKFB3 expression in both tumor cells and tumor endothelial cells was significantly correlated with poor prognosis. Multivariate analysis identified PFKFB3 expression as an independent prognostic factor. PFK15 suppressed proliferation of HCC cell line and tumor endothelial cells in vitro. In a subcutaneous tumor model of the HCC cell line with tumor endothelial cells, PFK15 suppressed tumor growth and induced apoptosis. Moreover, PFK15 treatment induced tumor vessel normalization, decreasing vessel diameter with pericyte attachment and improving vessel perfusion. High PFKFB3 expression in both tumor cells and tumor endothelial cells was identified as a novel prognostic marker in HCC. Targeting PFKFB3 via PFK15 might be a promising strategy for suppressing tumor growth and inducing tumor vessel normalization.

Long Non-Coding RNA BLACAT1 in Human Cancers.

Long non-coding RNAs (lncRNAs) are a cluster of RNAs with more than 200 nucleotides in length, which lack protein-coding capacity. They are important regulators of numerous cellular processes, including gene transcription, translation, and posttranslational modification, especially in tumor initiation and progression. Aberrant expression of lncRNA bladder cancer–associated transcript 1 (BLACAT1) has been reported in various human cancers and was usually associated with unfavorable prognosis. Previous studies have revealed that dysregulation of BLACAT1 could promote the proliferation and metastasis of cancer cells. In this review, we summarize the present understanding of the functions and underlying mechanisms of BLACAT1 in the occurrence and development of various human cancers and discuss the roles of this lncRNA in cancers, including its promising application as a prognostic biomarker or a novel therapeutic target for malignancies.

\u03b2-catenin S45F mutation results in apoptotic resistance

Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3, thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.

A nanobody targeting the LIN28:let-7 interaction fragment of TUT4 blocks uridylation of let-7

The LIN28:pre-let-7:TUTase ternary complex regulates pluripotency and oncogenesis by controlling processing of the let-7 family of microRNAs. The complex oligouridylates the 3' ends of pre-let-7 molecules, leading to their degradation via the DIS3L2 exonuclease. Previous studies suggest that components of this complex are potential therapeutic targets in malignancies that aberrantly express LIN28. In this study we developed a functional epitope selection approach to identify nanobody inhibitors of the LIN28:pre-let-7:TUT4 complex. We demonstrate that one of the identified nanobodies, Nb-S2A4, targets the 106-residue LIN28:let-7 interaction (LLI) fragment of TUT4. Nb-S2A4 can effectively inhibit oligouridylation and monouridylation of pre-let-7g in vitro. Expressing Nb-S2A4 allows maturation of the let-7 species in cells expressing LIN28, highlighting the therapeutic potential of targeting the LLI fragment.