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Novel Molecular Mechanisms Underlying Tumorigenesis and Innovative Therapeutic Approaches for Cancer-Fighting

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: closed (30 November 2020) | Viewed by 22006

Special Issue Editors

Department of Pharmacy, University of Naples Federico II, 80131 Napoli, Italy
Interests: cancer; chemoresistance; nucleolar stress; extra-ribosomal function of ribosomal proteins; cell cycle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

According to the World Health Organization, cancer is the most common cause of premature death in developed countries. Conventional cancer treatment involves the therapeutic application of chemotherapeutic agents associated with surgical therapy. However, the clinical outcome of this therapeutic approach can be unsatisfactory, especially in patients with advanced disease. Furthermore, common chemotherapeutic drugs show high levels of toxicity for normal cells, which is often associated with the development of chemoresistance. For these reasons, oncological research has focused on finding innovative therapies that increase the specificity of the treatment  and reduce their drawbacks. New therapeutic approaches for cancer treatment, currently under evaluation in many clinical trials worldwide, include but are not limited to: molecules targeting the nucleolus, natural antioxidants and phytochemicals in combination with common chemotherapeutic drugs, expression of genes triggering apoptosis, and/or tumor suppressors, targeted silencing mediated by siRNAs, and the nanodelivery of chemotherapeutics.

The combination of new and conventional approaches allows oncologists to select the best and most personalized therapy for cancer treatment.

This Special Issue is envisaged to document studies on the molecular mechanism underlying tumorigenesis and on innovative strategies for cancer treatment.

Dr. Annapina Russo
Dr. Giulia Russo
Guest Editors

Manuscript Submission Information

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Keywords

  • cancer
  • nucleolus
  • nucleolar stress
  • tumorigenesis
  • cancer therapy

Published Papers (8 papers)

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Editorial

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3 pages, 168 KiB  
Editorial
Novel Molecular Mechanisms Underlying Tumorigenesis and Innovative Therapeutic Approaches for Cancer-Fighting
by Annalisa Pecoraro, Giulia Russo and Annapina Russo
Int. J. Mol. Sci. 2023, 24(13), 10956; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310956 - 30 Jun 2023
Viewed by 531
Abstract
Remarkable advances have been made in cancer therapy; however, the high degree of cellular heterogeneity observed during cancer progression is the major driver in the development of resistant phenotypes upon treatment administration [...] Full article

Research

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27 pages, 7750 KiB  
Article
Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma
by Anna Barbato, Antonella Iuliano, Mariagrazia Volpe, Romina D’Alterio, Simona Brillante, Filomena Massa, Rossella De Cegli, Sabrina Carrella, Massimiliano Salati, Annapina Russo, Giulia Russo, Sara Riccardo, Davide Cacchiarelli, Mariaelena Capone, Gabriele Madonna, Paolo A. Ascierto, Brunella Franco, Alessia Indrieri and Pietro Carotenuto
Int. J. Mol. Sci. 2021, 22(4), 1801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041801 - 11 Feb 2021
Cited by 20 | Viewed by 3468
Abstract
MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles [...] Read more.
MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection. Full article
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18 pages, 5879 KiB  
Article
S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells
by Laura Mosca, Martina Pagano, Annalisa Pecoraro, Luigi Borzacchiello, Luigi Mele, Giovanna Cacciapuoti, Marina Porcelli, Giulia Russo and Annapina Russo
Int. J. Mol. Sci. 2021, 22(1), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010103 - 24 Dec 2020
Cited by 21 | Viewed by 2619
Abstract
Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential [...] Read more.
Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential in overcoming drug resistance in colon cancer cells devoid of p53. Results: In the present study, we demonstrated that S-adenosyl-l-methionine overcomes uL3-mediated drug resistance in p53 deleted colon cancer cells. In particular, we demonstrated that S-adenosyl-l-methionine causes cell cycle arrest at the S phase; inhibits autophagy; augments reactive oxygen species; and induces apoptosis in these cancer cells. Conclusions: Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes. Full article
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18 pages, 2143 KiB  
Article
Doxorubicin Improves Cancer Cell Targeting by Filamentous Phage Gene Delivery Vectors
by Effrosyni Tsafa, Kaoutar Bentayebi, Supachai Topanurak, Teerapong Yata, Justyna Przystal, Duriya Fongmoon, Nabil Hajji, Sajee Waramit, Keittisak Suwan and Amin Hajitou
Int. J. Mol. Sci. 2020, 21(21), 7867; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217867 - 23 Oct 2020
Cited by 14 | Viewed by 3882
Abstract
Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of [...] Read more.
Merging targeted systemic gene delivery and systemic chemotherapy against cancer, chemovirotherapy, has the potential to improve chemotherapy and gene therapy treatments and overcome cancer resistance. We introduced a bacteriophage (phage) vector, named human adeno-associated virus (AAV)/phage or AAVP, for the systemic targeting of therapeutic genes to cancer. The vector was designed as a hybrid between a recombinant adeno-associated virus genome (rAAV) and a filamentous phage capsid. To achieve tumor targeting, we displayed on the phage capsid the double-cyclic CDCRGDCFC (RGD4C) ligand that binds the alpha-V/beta-3 (αvβ3) integrin receptor. Here, we investigated a combination of doxorubicin chemotherapeutic drug and targeted gene delivery by the RGD4C/AAVP vector. Firstly, we showed that doxorubicin boosts transgene expression from the RGD4C/AAVP in two-dimensional (2D) cell cultures and three-dimensional (3D) tumor spheres established from human and murine cancer cells, while preserving selective gene delivery by RGD4C/AAVP. Next, we confirmed that doxorubicin does not increase vector attachment to cancer cells nor vector cell entry. In contrast, doxorubicin may alter the intracellular trafficking of the vector by facilitating nuclear accumulation of the RGD4C/AAVP genome through destabilization of the nuclear membrane. Finally, a combination of doxorubicin and RGD4C/AAVP-targeted suicide gene therapy exerts a synergistic effect to destroy human and murine tumor cells in 2D and 3D tumor sphere settings. Full article
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16 pages, 2969 KiB  
Article
Identification of Matrine as a Novel Regulator of the CXCR4 Signaling Axis in Tumor Cells
by Young Yun Jung, Jae-Young Um, Acharan S. Narula, Ojas A. Namjoshi, Bruce E. Blough, Alan Prem Kumar and Kwang Seok Ahn
Int. J. Mol. Sci. 2020, 21(13), 4731; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134731 - 02 Jul 2020
Cited by 12 | Viewed by 2202
Abstract
Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. [...] Read more.
Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy. Full article
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Review

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15 pages, 795 KiB  
Review
Therapeutic Potential of the Natural Compound S-Adenosylmethionine as a Chemoprotective Synergistic Agent in Breast, and Head and Neck Cancer Treatment: Current Status of Research
by Laura Mosca, Francesca Vitiello, Alessandra Coppola, Luigi Borzacchiello, Concetta Paola Ilisso, Martina Pagano, Michele Caraglia, Giovanna Cacciapuoti and Marina Porcelli
Int. J. Mol. Sci. 2020, 21(22), 8547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228547 - 13 Nov 2020
Cited by 15 | Viewed by 2687
Abstract
The present review summarizes the most recent studies focusing on the synergistic antitumor effect of the physiological methyl donor S-adenosylmethionine (AdoMet) in association with the main drugs used against breast cancer and head and neck squamous cell carcinoma (HNSCC), two highly aggressive and [...] Read more.
The present review summarizes the most recent studies focusing on the synergistic antitumor effect of the physiological methyl donor S-adenosylmethionine (AdoMet) in association with the main drugs used against breast cancer and head and neck squamous cell carcinoma (HNSCC), two highly aggressive and metastatic malignancies. In these two tumors the chemotherapy approach is recommended as the first choice despite the numerous side effects and recurrence of metastasis, so better tolerated treatments are needed to overcome this problem. In this regard, combination therapy with natural compounds, such as AdoMet, a molecule with pleiotropic effects on multiple cellular processes, is emerging as a suitable strategy to achieve synergistic anticancer efficacy. In this context, the analysis of studies conducted in the literature highlighted AdoMet as one of the most effective and promising chemosensitizing agents to be taken into consideration for inclusion in emerging antitumor therapeutic modalities such as nanotechnologies. Full article
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21 pages, 1492 KiB  
Review
Role of Autophagy in Cancer Cell Response to Nucleolar and Endoplasmic Reticulum Stress
by Annalisa Pecoraro, Martina Pagano, Giulia Russo and Annapina Russo
Int. J. Mol. Sci. 2020, 21(19), 7334; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197334 - 04 Oct 2020
Cited by 19 | Viewed by 3472
Abstract
Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation [...] Read more.
Eukaryotic cells are exposed to many internal and external stimuli that affect their fate. In particular, the exposure to some of these stimuli induces stress triggering a variety of stress responses aimed to re-establish cellular homeostasis. It is now established that the deregulation of stress response pathways plays a central role in cancer initiation and progression, allowing the adaptation of cells to an altered state in the new environment. Autophagy is a tightly regulated pathway which exerts “housekeeping” role in physiological processes. Recently, a growing amount of evidence highlighted the crucial role of autophagy in the regulation of integrated stress responses, including nucleolar and endoplasmic reticulum. In this review, we attempt to afford an overview of the complex role of nucleolar and endoplasmic reticulum stress-response mechanisms in the regulation of autophagy in cancer and cancer treatment. Full article
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18 pages, 1929 KiB  
Review
Long Non-Coding RNAs as Strategic Molecules to Augment the Radiation Therapy in Esophageal Squamous Cell Carcinoma
by Uttam Sharma, Tushar Singh Barwal, Varnali Acharya, Karuna Singh, Manjit Kaur Rana, Satyendra Kumar Singh, Hridayesh Prakash, Anupam Bishayee and Aklank Jain
Int. J. Mol. Sci. 2020, 21(18), 6787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186787 - 16 Sep 2020
Cited by 13 | Viewed by 2538
Abstract
Intrinsic resistance to ionizing radiation is the major impediment in the treatment and clinical management of esophageal squamous cell carcinoma (ESCC), leading to tumor relapse and poor prognosis. Although several biological and molecular mechanisms are responsible for resistance to radiotherapy in ESCC, the [...] Read more.
Intrinsic resistance to ionizing radiation is the major impediment in the treatment and clinical management of esophageal squamous cell carcinoma (ESCC), leading to tumor relapse and poor prognosis. Although several biological and molecular mechanisms are responsible for resistance to radiotherapy in ESCC, the molecule(s) involved in predicting radiotherapy response and prognosis are still lacking, thus requiring a detailed understanding. Recent studies have demonstrated an imperative correlation amongst several long non-coding RNAs and their involvement in complex cellular networks like DNA damage and repair, cell cycle, apoptosis, proliferation, and epithelial-mesenchymal transition. Additionally, accumulating evidence has suggested abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy effects in tumor cells’ sensitivity. Thus, lncRNAs indeed represent unique molecules that can influence tumor cell susceptibility for various clinical interventions. On this note, herein, we have summarized the current status of lncRNAs in augmenting resistance/sensitivity in ESCC against radiotherapy. In addition, we have also discussed various strategies to increase the radiosensitivity in ESCC cells under clinical settings. Full article
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