Molecular Cancer Research最新文献

Although transcriptomic studies have stratified pancreatic ductal adenocarcinoma (PDAC) into clinically relevant subtypes, classic or basal-like, further research is needed to identify the transcriptional regulators of each subtype. Previous studies identified HNF4α as a key regulator of the classic subtype. Still, the distinct contributions of its isoforms (P1 and P2), which display dichotomous functions in normal development and gastrointestinal malignancies, remain unexplored. In this study, we show that HNF4α-positive human PDAC tumors exhibit uniform expression of P2 isoforms but variable expression of P1 isoforms. To dissect the roles of each isoform in PDAC, we performed functional, transcriptomic, and epigenetic analyses after exogenous expression in HNF4α-negative models or CRISPRi-mediated knockdown of endogenous isoforms. We demonstrated that P1 isoforms are less compatible with growth and stronger transcriptional regulators than P2. Despite both isoforms sharing a common DNA-binding domain, P1 isoforms displayed stronger binding at HNF4α target genes, resulting in increased transcriptional activity. These findings provide a detailed characterization of HNF4α P1 and P2 isoforms and their distinct roles in PDAC biology.

Implications: HNF4α isoforms exhibit heterogeneous expression in PDAC and have distinct effects on proliferation and gene expression, including markers of clinically relevant molecular subtypes.

Intrahepatic cholangiocarcinoma (ICC) is the second most common liver cancer. LINC00519 plays a prominent role in the progression of numerous cancers. To explore the molecular mechanism of LINC00519 in ICC, the expressions of LINC00519, hsa-miR-22-3p, and MECOM in ICC were assessed using the ENCORI database and qRT-PCR. The biological functions of LINC00519 in ICC were examined using a clone formation experiment, Transwell analysis, flow cytometry, and Western blot. Meanwhile, the mechanism of LINC00519 in ICC was determined by a dual-luciferase reporter assay. Results showed that LINC00519 and MECOM were highly expressed in ICC, whereas hsa-miR-22-3p was decreased. Functionally, silencing LINC00519 weakened ICC cell proliferation and migration and induced cell apoptosis. Also, LINC00519 knockdown repressed the PI3K/AKT (protein kinase B) pathway. Mechanistically, LINC00519 acted as a competitive endogenous RNA to target MECOM by sponging hsa-miR-22-3p. Meanwhile, rescue assays further proved that low LINC00519 expression restrained ICC cell proliferation and migration and accelerated apoptosis through the PI3K/AKT pathway by miR-22-3p/MECOM. In conclusion, this research revealed a novel LINC00519/hsa-miR-22-3p/MECOM regulatory axis and PI3K/AKT pathway that modulated ICC progression.

Implications: This study deepens the understanding of the noncoding RNA regulatory network in ICC and provides potential targets for the diagnosis and targeted therapy of ICC.

Long noncoding RNAs act as modulators, with significant influence on a wide array of biological functions. They form an extensive communication network between genes and contribute to the pathophysiology of various human diseases, especially cancer. A growing body of research has demonstrated that long noncoding RNAs, acting either as promoters or inhibitors of oncogenesis, are intricately linked to the initiation and progression of cancer. Metastasis-associated colon cancer 1 antisense RNA1 (MACC1-AS1) is a newly identified long noncoding RNA that is abnormally expressed in various types of human tumors. Poor clinical characteristics, such as larger tumor size, advanced tumor stage, lymph node metastasis, and a lower overall survival rate, are linked to the overexpression of MACC1-AS1. MACC1-AS1 exerts a complex regulatory function: It acts as a competitive RNA, interacts with multiple proteins, and influences diverse pathways, leading to tumor development. It is essential to note the decreased efficacy of conventional chemotherapy drugs, which diminishes the efficacy of cancer treatment. Ongoing research has been highlighting the multifaceted functions of MACC1-AS1, and thus, it is required to unravel its exact molecular mechanisms. In this overarching review, we explore the significance of MACC1-AS1 as a potential cancer treatment target and biomarker. This study can potentially play an important role in the advancement of the field and confirm its potential clinical applicability.

Human glioblastoma (GBM) is a remarkable example of a highly aggressive and untreatable tumor. A formidable challenge in treating GBM is its extensive intratumor heterogeneity, which traditional bulk tissue analysis fails to capture. Fluorescence-guided multiple sampling, utilizing 5-aminolevulinic acid for tumor visualization, offers objective tumor tissue identification and enhanced spatial resolution. In this study, we present a perspective on a novel "spatial-in-spatial" approach that enables comprehensive analysis of tumor areas and their microenvironment-at macroscopic and microscopic levels-by combining fluorescence-guided multiple sampling with spatial-omics technologies. This perspective discusses how this integrated methodology has the potential to advance our understanding of GBM biology through the high-resolution, multidimensional characterization of tumor heterogeneity and identification of novel, area-specific therapeutic targets.

Histone citrullination is catalyzed by peptidyl-arginine deiminases (PAD) that play a role in gene regulation, and several specific inhibitors have been developed. However, the clinical significance, molecular mechanisms of histone citrullination and PADs, and effects of PAD inhibitors in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study aimed to investigate the role and potential molecular mechanisms of PADs in PDAC. Histone citrullination was upregulated and strongly associated with the nuclear expression of PAD2, one of the PAD family, in human PDAC tissues, correlating with aggressiveness and poor prognosis. PAD2 overexpression increased PDAC cell proliferation, whereas its knockdown had the opposite effect in vitro. PAD2 was recruited to the promoter regions of PRUNE1 and E2F1, resulting in the activation of their mRNA expression via increased histone citrullination and chromatin accessibility. PAD2 overexpression enhanced tumorigenicity and increased PRUNE1 expression and M2 tumor-associated macrophage (M2 TAM) infiltration in vivo. PAD2 inhibitor suppressed the growth and tumorigenicity of PAD2-expressing PDAC mouse models by reducing PRUNE1 expression and M2 macrophage infiltration. Pad2 knockdown and PAD inhibitor treatment showed similar effects in syngeneic mouse models. The triple-high expression of nuclear PAD2, PRUNE1, and the M2 TAM marker CD206 may serve as independent adverse prognostic factors for human PDAC. Conclusively, PAD2-mediated histone citrullination drives PDAC progression by epigenetically regulating downstream target genes and influencing the tumor microenvironment. The PAD2-PRUNE1-M2 TAM axis presents a promising therapeutic target and prognostic indicator for PDAC.

Implications: Elevated PAD2 expression promotes PDAC progression by epigenetically activating PRUNE1 and enhancing M2 macrophage polarization.

Integrin α5β1 and αv cross-talk in chemotaxis, and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAbα5β1/αv inactivates pathologic mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses Yes-associated protein, β-catenin, and focal adhesion kinase nuclear localization compared with monospecific integrin α5β1 and αv antibody controls in basal-type androgen receptor-negative prostate cancer cells. Dual integrin αv and α5 knockdown alone phenocopied the BsAbα5β1/αv effect. Following BsAbα5β1/αv treatment, Assay for Transposase-Accessible Chromatin using sequencing studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA sequencing indicated downregulation of Myc/E2F, TGF-β, and epithelial-mesenchymal transition and upregulation of type I and II IFN transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and NK cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. αv integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and Deutsches Krebsforschungszentrum early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancers and define a novel therapeutic strategy that controls critical immunosuppressive pathways.

Implications: Dual integrin α5β1/αv targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signatures of basal-type prostate cancer with induction of immunologic tumor control.

We identified a long noncoding RNA, LINC01235, with significant enrichment in luminal progenitor (LP)-like cells in triple-negative breast cancer (TNBC) organoids and cell lines. Antisense-mediated knockdown or genetic knockout of LINC01235 in TNBC cell lines led to a decline in cell proliferation and adversely affected the ability to form organoids. A comprehensive co-expression analysis, leveraging The Cancer Genome Atlas data, revealed a distinct correlation between LINC01235 expression and the expression of NFIB, a neighboring gene encoding a transcription factor. Subsequent CRISPR knockout or antisense oligonucleotide-mediated knockdown studies demonstrated an upstream regulatory role of LINC01235 over NFIB. Moreover, our investigations demonstrated that LINC01235 regulates the Notch pathway through NFIB, and chromatin isolation by RNA purification followed by qPCR results indicated the direct binding of LINC01235 to the NFIB promoter. Our findings demonstrate that LINC01235 positively regulates NFIB transcription, which in turn modulates the Notch pathway, influencing LP-like cell proliferation in breast cancer progression. This study highlights a pivotal role of LINC01235 in TNBC and its potential as a therapeutic target.

Implications: This study demonstrates the central role of LINC01235 as an upstream positive regulator of NFIB and the Notch signaling pathway to induce the production of LP-like cells in TNBC.

Myeloid-derived suppressor cells (MDSCs) are characterized by abnormal phenotypes, high heterogeneity, and immunosuppressive function. MDSCs are critical components in the tumor immune microenvironment, contributing to cancer progression by inhibiting T cells, B cells, NK cells, and dendritic cells while promoting regulatory T cells, tumor-associated macrophages, and Th17 cells. Beyond immunosuppression, MDSCs facilitate tumor angiogenesis, tumor cell stemness, epithelial-mesenchymal transition, and premetastatic niche formation. Current therapeutic strategies targeting MDSCs include depletion, functional inhibition, induction of differentiation, and disruption of MDSC recruitment and activation. Various therapeutic agents-including chemotherapeutics, mAbs, small-molecule inhibitors, and natural compounds-have shown efficacy in modulating MDSC activity. Combining MDSC-targeted therapy with existing immunotherapies, such as immune checkpoint inhibitors, may further improve antitumor responses.

HER2 amplification or mutation accounts for 25% of patients with breast cancer that can advance to metastatic disease. Therefore, it is important to identify novel genes that mediate metastasis in HER2+ breast cancer. In this study, we describe a new metastatic suppressor gene, class II phosphatidylinositol 3-kinase β (Pi3kc2β), through in vivo CRISPR-Cas9 library screening of a custom-designed library targeting genes implicated in autophagy using murine HER2+ breast cancer (N418) cells. We further showed that PI3KC2β knockout N418 cells increased their migration and invasion in vitro and lung metastasis in both spontaneous and experimental metastasis assays in vivo. Analysis of databases and tissue samples from patients with breast cancer correlated lower expression of PI3KC2β with decreased metastasis, overall survival, and relapse-free survival. Further, PI3KC2β deletion induced the activation of mTORC1 signaling, independent of affecting its kinase activity. Mechanistically, we found that PI3KC2β forms a complex with intersectin 1 (ITSN1) and raptor that could be decreasing the stability of raptor, and deletion of either PI3KC2β or ITSN1 led to increased raptor levels and mTORC1 signaling. Lastly, rapamycin treatment reduced the migration and invasion of PI3KC2β knockout tumor cells in vitro and their lung metastasis in vivo, supporting an important role of the mTORC1 pathway. Together, our results identify PI3KC2β as a suppressor of HER2+ breast cancer metastasis by negatively regulating mTORC1 signaling by affecting its complex formation with ITSN1 and raptor.

Implications: Our findings revealed PI3KC2β as a new metastasis suppressor for HER2+ breast cancer, which might serve as a potential diagnostic and therapeutic target for the disease.

Protein kinase C δ (PKCδ) regulates DNA repair and apoptosis, and inhibition of PKCδ provides robust radioprotection. In this study, we show that depletion of PKCδ increases mitochondrial reactive oxygen species (ROS) production and induces an endogenous antioxidant response through nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in decreased basal and irradiation (IR)-induced DNA damage and cell death. Radioprotection by PKCδ depletion can be reversed with the free radical scavenger, N-acetyl-L-cysteine, indicating an essential role for the antioxidant response. Whereas mitochondrial mass and membrane potential are increased in PKCδ-depleted cells, oxidative phosphorylation and the activity of electron transport chain complex I and complex III are reduced, suggesting that electron transport chain dysfunction is the source of the increased mitochondrial ROS. The antioxidant response induced by PKCδ depletion is mediated through Sirtuin 6 (SIRT6) and Nrf2. Increased mitochondrial ROS and Nrf2 activation are reversed in PKCδ/SIRT6 double knockdown cells, indicating a central role for SIRT6 in PKCδ-regulated DNA repair and cell death. Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.

Implications: Regulation of the endogenous antioxidant state through manipulation of the PKCδ/SIRT6 signaling pathway may be a novel clinical approach for protection of healthy tissues in patients undergoing IR therapy.