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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 1 December 2025 | Viewed by 9506

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Dr. Giovanna Casili

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Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31-98166 Messina, Italy
Interests: neuroinflammation; neurodegeneration; inflammation; oncology; brain tumor
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Dear Colleagues,

Oncology research continues to reveal the molecular signatures that define tumor characteristics and behavior, with the focus increasingly shifting toward the complex molecular pathways implicated in tumorigenesis, cancer cell proliferation, inflammation and angiogenesis, tissue infiltration, and dissemination to distant sites. New research should focus on better investigating the molecular mechanisms that promote cancer and on the development of efficient therapeutic and pharmacological interventions. For this Special Issue, we welcome research and review articles focusing on the diverse molecular mechanisms implicated in different steps of carcinogenesis, which could serve as therapeutic targets.

Dr. Giovanna Casili
Guest Editor

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Keywords

molecular pathway involved in tumorigenesis
cancer therapy
targeted therapy
anticancer drugs
brain cancer
oral cancer
gastrointestinal cancer

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Related Special Issues

Novel Molecular Pathways in Oncology in International Journal of Molecular Sciences (13 articles)
Novel Molecular Pathways in Oncology 2.0 in International Journal of Molecular Sciences (10 articles)

Published Papers (10 papers)

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Research

Jump to: Review

13 pages, 2026 KB

Open AccessArticle

miR-28-5p and miR-708-5p Share a Common Seed with Different Functions in Lung Cancer Patients

by Cristina Alexandra Ciocan, Cecilia Bica, Liviuta Budisan, Lajos Raduly, Sergiu Chira, Claudia-Cristina Burz, Ovidiu Farc, Antonia Harangus, Marioara Simon, Constantin-Ioan Busuioc, Stefan Strilciuc, Cornelia Braicu and Ioana Berindan-Neagoe

Int. J. Mol. Sci. 2025, 26(21), 10364; https://doi.org/10.3390/ijms262110364 - 24 Oct 2025

Viewed by 295

Abstract

Lung cancer remains the leading cause of cancer-related mortality worldwide, accounting for nearly 1.8 million deaths annually. The present study aimed to investigate the role of miR-28-5p and miR-708-5p in lung cancer and to analyze the relationship between target gene profiles and transcriptional factor regulation. Both miRNAs that share a common seed sequence were found to be overexpressed in a cohort of 32 paired tumor and adjacent normal tissue samples collected from patients diagnosed at advanced stages (III and IV) of disease. Data from the dbDEMC database revealed that miR-28-5p exhibited variable expression across lung cancer subtypes, whereas miR-708-5p showed consistent overexpression, reinforcing its potential clinical diagnostic significance. Using the TransmiR database, we identified complex TF–miRNA regulatory networks, with both shared and distinct transcription factors controlling miR-28-5p and miR-708-5p. Pathway enrichment analysis indicated that these miRNAs regulate several cancer-associated pathways, including ECM–receptor interaction, adherens junctions, and Hippo signaling. Overall, our findings suggest that miR-708-5p may have a potential clinical application in lung cancer. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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21 pages, 4008 KB

Open AccessArticle

Combined Treatment of Sodium Butyrate and Bromelain Enhanced Anticancer Effects in Colorectal Cancer Cell Lines: A Promising Therapeutic Approach

by Rocío Olivera-Salazar, Pedro Villarejo Campos, Rocío Barrueco Gutiérrez, Luz Vega-Clemente, Luis Javier Serrano, Soledad García Gómez-Heras, Damián García-Olmo and Mariano García-Arranz

Int. J. Mol. Sci. 2025, 26(19), 9803; https://doi.org/10.3390/ijms26199803 - 8 Oct 2025

Viewed by 568

Abstract

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, with few effective treatment options and substantial associated side effects. As a result, there is growing interest in therapeutic alternatives that reduce toxicity. Natural compounds such as sodium butyrate (NaB), a microbial metabolite of dietary fiber, and bromelain, a proteolytic enzyme from pineapple, have shown individual anticancer properties. However, their combined effect in CRC remains underexplored. This study investigates the synergistic potential of NaB and bromelain in colorectal cancer cell lines, focusing on their ability to inhibit proliferation, induce apoptosis, and modulate key molecular pathways. Findings reveal that co-treatment enhances antitumor activity in vitro, suggesting a promising and safer therapeutic strategy for CRC. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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14 pages, 3043 KB

Open AccessArticle

Antitumor Activity by an Anti-CD44 Variant 9 Monoclonal Antibody in Gastric and Colorectal Cancer Xenograft Models

by Mayuki Tawara, Hiroyuki Suzuki, Tomokazu Ohishi, Mika K. Kaneko and Yukinari Kato

Int. J. Mol. Sci. 2025, 26(18), 9170; https://doi.org/10.3390/ijms26189170 - 19 Sep 2025

Cited by 1 | Viewed by 666

Abstract

CD44 variants (CD44v) play essential roles in the promotion of tumor metastasis, maintenance of cancer stem cell properties, and resistance to treatments. Therefore, the development of anti-CD44v mAbs is essential for targeting CD44v-positive tumor cells. An anti-CD44v9 mAb, C₄₄Mab-1 (mouse, IgG₁, kappa), was previously established. C₄₄Mab-1 recognizes the variant exon 9-encoded region and applies to multiple research techniques. A mouse IgG_2a version of C₄₄Mab-1 (C₄₄Mab-1-mG_2a) was generated to evaluate the in vitro and in vivo antitumor activities using gastric and colorectal cancer cell lines. C₄₄Mab-1-mG_2a showed a reactivity to CD44v3–10-overexpressed Chinese hamster ovary-K1 (CHO/CD44v3–10), gastric cancer MKN45, and colorectal cancer COLO205 in flow cytometry. C₄₄Mab-1-mG_2a exhibited both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against CHO/CD44v3–10, MKN45, and COLO205. Furthermore, administration of C₄₄Mab-1-mG_2a significantly suppressed CHO/CD44v3–10, MKN45, and COLO205 xenograft tumor growth compared with control mouse IgG_2a. These results indicated that C₄₄Mab-1-mG_2a, which possesses ADCC/CDC activities, could be applied to the mAb-based therapy against CD44v9-positive carcinomas. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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27 pages, 3114 KB

Open AccessArticle

Proteomic Analysis Uncovers Enhanced Inflammatory Phenotype and Distinct Metabolic Changes in IDH1 Mutant Glioma Cells

by Sigrid Ravn Berg, Alessandro Brambilla, Lars Hagen, Animesh Sharma, Cathrine Broberg Vågbø, Nina Beate Liabakk, Miroslava Kissova, Miquel Arano Barenys, Magnar Bjørås, Sverre Helge Torp and Geir Slupphaug

Int. J. Mol. Sci. 2025, 26(18), 9075; https://doi.org/10.3390/ijms26189075 - 18 Sep 2025

Cited by 1 | Viewed by 800

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influencing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wild-type IDH1. We quantified over 6000 protein groups per model, identifying 1594 differentially expressed proteins in PD-AS (IDH1_MUT) vs. PD-GB (IDH1_WT) and 904 in U87_MUT vs. U87_WT. Both IDH1_MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microenvironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87_MUT cells retained oxidative phosphorylation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1_MUT models, particularly those involved in homologous recombination. In contrast, RB1 and ASMTL were strongly upregulated in both IDH1_MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins regulating histone methylation in IDH1_MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to the recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways relevant to glioma progression and therapeutic targeting, but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation status. While proteome profiling provides valuable insights, a comprehensive understanding of IDH1_MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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13 pages, 3320 KB

Open AccessArticle

Regulation of Human Lung Adenocarcinoma Cell Proliferation by LncRNA AFAP-AS1 Through the miR-508/ZWINT Axis

by Sultan F. Kadasah and Abdulaziz M. S. Alqahtani

Int. J. Mol. Sci. 2025, 26(13), 6532; https://doi.org/10.3390/ijms26136532 - 7 Jul 2025

Cited by 1 | Viewed by 722

Abstract

Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung adenocarcinoma cell proliferation via miR-508-3p and ZWINT. Human lung adenocarcinoma A549 cells were transfected with siRNA constructs against AFAP1-AS1 (si-AFAP1-AS1) to silence its expression. Cell proliferation was evaluated via CCK-8 and colony-forming assays. Apoptosis was assessed using AO/EB staining, and invasion was determined via Transwell assay. The interaction between AFAP1-AS1, miR-508-3p, and ZWINT was confirmed via dual luciferase reporter assay and qRT-PCR analysis. Data were analysed using appropriate statistical tests. AFAP1-AS1 was significantly upregulated in lung adenocarcinoma cells compared to normal BEAS-2B cells. Silencing of AFAP1-AS1 resulted in a marked reduction in A549 cell proliferation and colony development, as observed in CCK-8 and colony formation assays. The AO/EB assay showed a significant increase in apoptosis (30 ± 4.4%) in si-AFAP1-AS1 transfected cells compared to control si-NC (3 ± 1.2%). In addition, knockdown of AFAP1-AS1 led to an upsurge of pro-apoptotic Bax and decline of anti-apoptotic Bcl-2 expression. The dual luciferase assay established the interaction between AFAP1-AS1 and miR-508-3p. Furthermore, ZWINT, identified as a target of miR-508-3p, was significantly upregulated in lung adenocarcinoma tissues. Overexpression of ZWINT rescued the inhibitory effects of AFAP1-AS1 silencing on cell proliferation, colony formation, and apoptosis, while also reversing the reduction in cell invasion. AFAP1-AS1 accelerates the development of lung adenocarcinoma by cell proliferation, apoptosis, and invasion via the miR-508-3p/ZWINT axis. Thus, targeting AFAP1-AS1 or its downstream regulatory axis could offer novel therapeutic approaches in lung adenocarcinoma treatment. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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15 pages, 3764 KB

Open AccessArticle

Apoptosis-Inducing and Proliferation-Inhibiting Effects of Doramectin on Mz-ChA-1 Human Cholangiocarcinoma Cells

by Yunfang Zhang, Wei Wu, Yan Shi, Yuehong Huang, Ting Dai, Lina Ke, Lizhu Chen, Mingliang Chen and Qin Wang

Int. J. Mol. Sci. 2024, 25(24), 13440; https://doi.org/10.3390/ijms252413440 - 15 Dec 2024

Viewed by 1437

Abstract

Cholangiocarcinoma is a malignant tumor that emerges in the intrahepatic or extrahepatic bile ducts. Doramectin (DOR), a third-generation derivative of avermectins (AVMs), is renowned for its low toxicity and high efficiency. However, no research has hitherto focused on the anti-cholangiocarcinoma effects of these drugs. In this study, we undertook a preliminary exploration of the mechanism through which DOR inhibits the viability of human cholangiocarcinoma cells (Mz-ChA-1) via transcriptome analysis and molecular validation at the cellular level. The results indicated that DOR could suppress the growth and proliferation of Mz-ChA-1 cells in a dose-dependent manner. Moreover, it significantly diminished their migration and invasion abilities. Cell cycle analysis disclosed arrest in the G1 phase, accompanied by an increase in p21 expression and a decrease in the levels of the cyclin E1 and CDK2 proteins. Additionally, DOR induced apoptosis via the ROS-triggered mitochondrial pathway. This was attested by an elevation in the BAX/BCL-2 ratio, the activation of caspase 3/7 and the cleavage of PARP1. These mechanistic insights underscore DOR’s potential as a therapeutic agent against cholangiocarcinoma Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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16 pages, 6325 KB

Open AccessArticle

Echium amoenum and Rosmarinic Acid Suppress the Growth and Metastasis of Gastric Cancer AGS Cells by Promoting Apoptosis and Inhibiting EMT

by Mahdieh Ahmadi, Hong Lae Kim, So Jin Park and Hye Jin Jung

Int. J. Mol. Sci. 2024, 25(23), 12909; https://doi.org/10.3390/ijms252312909 - 30 Nov 2024

Cited by 2 | Viewed by 1745

Abstract

Gastric cancer (GC) ranks as the fifth most prevalent cancer globally. Owing to the absence of early manifest symptoms, it is difficult to diagnose GC until it has metastasized to other organs. Hence, the prevention and treatment of GC have become major concerns for patients. Echium amoenum, a traditional medicinal plant from the Boraginaceae family, exhibits various biological activities. Although recent studies have reported the anticancer properties of E. amoenum, its effects and mechanisms of action on GC cells are not yet fully understood. This study examined the anticancer effects of the ethyl acetate extract of E. amoenum (EAEC) and its main active ingredient, rosmarinic acid (RA), in GC AGS cells. EAEC and RA suppressed AGS cell growth by inducing apoptosis through caspase mediation and inhibited AGS cell metastasis by influencing the expression of crucial epithelial–mesenchymal transition (EMT) biomarkers. Furthermore, the anti-growth and anti-metastatic effects of EAEC and RA on AGS cells involved inactivation of the STAT3, AKT, and ERK1/2 pathways. Additionally, RA notably inhibited the in vivo tumor growth in AGS cells. Overall, these results indicate that EAEC and RA could serve as potential anticancer and anti-metastasis agents for GC. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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Review

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26 pages, 2235 KB

Open AccessReview

Vascular Disruption Therapy as a New Strategy for Cancer Treatment

by Jesús Gómez-Escudero, Patricia Berlana-Galán, Elena Guerra-Paes, Irene Torre-Cea, Laura Marcos-Zazo, Iván Carrera-Aguado, Daniel Cáceres-Calle, Fernando Sánchez-Juanes and José M. Muñoz-Félix

Int. J. Mol. Sci. 2025, 26(20), 10085; https://doi.org/10.3390/ijms262010085 - 16 Oct 2025

Viewed by 537

Abstract

A functional blood vessel network is required to deliver oxygen and nutrients to the cancer cells for their growth. Angiogenesis, the formation of new blood vessels from pre-existing ones, is one of the major mechanisms to create this vascular network. Anti-angiogenic therapy was conceived as the inhibition of the cellular and molecular players involved in tumor angiogenesis such as vascular endothelial growth factor and its main receptors. Due to limitations of this therapy, different approaches of vessel modulation such as vascular normalization or vascular promotion have been studied showing benefits in different tumor models and clinical trials. In contrast to anti-angiogenic therapy, which inhibits the blood vessels that are being formed, vascular disruption therapy aims to destroy already formed tumor vessels. These malignant vascular structures differ from other blood vessels in terms of endothelial cell states, pericyte coverage and basement membrane development. The molecules used for vascular disruption are microtubule-binding molecules, flavonoids that induce endothelial cell apoptosis or molecules vectorized to endothelial receptors. Many vascular disruption agents have been tested in clinical trials showing some promising results, but with some limitations that include resistant rim cells or the development of hypoxia that induces cancer regrowth and poor delivery of the anti-tumor agents. The main objective of this review is to focus on vascular disruption agents therapy, novel molecules, new ways to overcome therapy resistance to them, current clinical status and, especially, the upcoming challenges and applications of these molecules. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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30 pages, 1765 KB

Open AccessReview

Adipocyte–Tumor Interactions in the Bone Marrow Niche: Implications for Metastasis and Therapy

by Alhomam Dabaliz, Mohammad Nawar Al Hakawati, Najmuddeen Alrashdan, Sarah Alrashdan, Mohamad Bakir and Khalid S. Mohammad

Int. J. Mol. Sci. 2025, 26(19), 9781; https://doi.org/10.3390/ijms26199781 - 8 Oct 2025

Viewed by 1058

Abstract

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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14 pages, 2763 KB

Open AccessReview

Molecular Crosstalk Between RUNX2 and HIF-1α in Osteosarcoma: Implications for Angiogenesis, Metastasis, and Therapy Resistance

by Anuja Gajanan Magar, Vivek Kumar Morya and Kyu-Cheol Noh

Int. J. Mol. Sci. 2025, 26(15), 7642; https://doi.org/10.3390/ijms26157642 - 7 Aug 2025

Viewed by 1123

Abstract

Runt-related transcription factor-2 (RUNX2) is an integral player in osteogenesis and is highly expressed in osteosarcoma. Emerging evidence suggests that aberrant RUNX2 expression is a key factor in osteosarcoma oncogenesis. Patients with advanced stages of osteosarcoma overexpressing RUNX2 are more likely to have high tumour grades, metastasis, and lower overall or progression-free survival rates. Thus, RUNX2 is considered a potential candidate for targeted therapy of osteosarcoma. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor involved in the regulation of cellular reprogramming in response to hypoxia. Overexpression of HIF-1α decreases overall survival, disease-free survival, and chemotherapy response and promotes tumour stage and metastasis. Hence, our review focused on highlighting the intricate network between RUNX2 and HIF-1α, which support each other or may work synergistically to develop resistance to therapy and osteosarcoma progression. An in-depth understanding of these two important tumour progression markers is required. Therefore, this review focuses on the role of RUNX2 and HIF-1α in the alteration of the tumour microenvironment, which further promotes angiogenesis, metastasis, and resistance to therapy in osteosarcoma. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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