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20 pages, 4085 KiB

Open AccessArticle

Comprehensive RNA-Seq Gene Co-Expression Analysis Reveals Consistent Molecular Pathways in Hepatocellular Carcinoma across Diverse Risk Factors

by Nicholas Dale D. Talubo, Po-Wei Tsai and Lemmuel L. Tayo

Biology 2024, 13(10), 765; https://doi.org/10.3390/biology13100765 - 26 Sep 2024

Viewed by 993

Abstract

Hepatocellular carcinoma (HCC) has the highest mortality rate and is the most frequent of liver cancers. The heterogeneity of HCC in its etiology and molecular expression increases the difficulty in identifying possible treatments. To elucidate the molecular mechanisms of HCC across grades, data [...] Read more.

Hepatocellular carcinoma (HCC) has the highest mortality rate and is the most frequent of liver cancers. The heterogeneity of HCC in its etiology and molecular expression increases the difficulty in identifying possible treatments. To elucidate the molecular mechanisms of HCC across grades, data from The Cancer Genome Atlas (TCGA) were used for gene co-expression analysis, categorizing each sample into its pre-existing risk factors. The R library BioNERO was used for preprocessing and gene co-expression network construction. For those modules most correlated with a grade, functional enrichments from different databases were then tested, which appeared to have relatively consistent patterns when grouped by G1/G2 and G3/G4. G1/G2 exhibited the involvement of pathways related to metabolism and the PI3K/Akt pathway, which regulates cell proliferation and related pathways, whereas G3/G4 showed the activation of cell adhesion genes and the p53 signaling pathway, which regulates apoptosis, cell cycle arrest, and similar processes. Module preservation analysis was then used with the no history dataset as the reference network, which found cell adhesion molecules and cell cycle genes to be preserved across all risk factors, suggesting they are imperative in the development of HCC regardless of potential etiology. Through hierarchical clustering, modules related to the cell cycle, cell adhesion, the immune system, and the ribosome were found to be consistently present across all risk factors, with distinct clusters linked to oxidative phosphorylation in viral HCC and pentose and glucuronate interconversions in non-viral HCC, underscoring their potential roles in cancer progression. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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13 pages, 2051 KiB

Open AccessArticle

Tumorspheres as In Vitro Model for Identifying Predictive Chemoresistance and Tumor Aggressiveness Biomarkers in Breast and Colorectal Cancer

by Toni Martinez-Bernabe, Pere Miquel Morla-Barcelo, Lucas Melguizo-Salom, Margalida Munar-Gelabert, Alba Maroto-Blasco, Margalida Torrens-Mas, Jordi Oliver, Pilar Roca, Mercedes Nadal-Serrano, Daniel Gabriel Pons and Jorge Sastre-Serra

Biology 2024, 13(9), 724; https://doi.org/10.3390/biology13090724 - 15 Sep 2024

Viewed by 1166

Abstract

Chemoresistance remains a major challenge in the treatment of breast and colorectal cancer. For this reason, finding reliable predictive biomarkers of response to chemotherapy has become a significant research focus in recent years. However, validating in vitro results may be problematic due to [...] Read more.

Chemoresistance remains a major challenge in the treatment of breast and colorectal cancer. For this reason, finding reliable predictive biomarkers of response to chemotherapy has become a significant research focus in recent years. However, validating in vitro results may be problematic due to the outcome heterogeneity. In this study, we evaluate the use of tumorspheres as an in vitro model for validating biomarkers of chemoresistance in breast and colorectal cancer. Our investigation highlights the crucial role of inflammation-related pathways in modulating the response to chemotherapy. Using in silico approaches, we identified specific markers elevated in responders versus non-responders patients. These markers were consistently higher in three-dimensional (3D) tumorsphere models compared to traditional adherent cell culture models. Furthermore, the number of tumorspheres from breast and colorectal cancer cells increased in response to cisplatin and oxaliplatin treatment, respectively, whereas cell viability decreased in adherent cell culture. This differential response underscores the importance of the 3D tumorsphere model in mimicking the tumor microenvironment more accurately than adherent cell culture. The enhanced chemoresistance observed in the 3D tumorspheres model and their correlation of data with the in silico study suggest that 3D culture models are a better option to approach the in vivo model and also to validate in silico data. Our findings indicate that tumorspheres are an ideal model for validating chemoresistance biomarkers and exploring the interplay between inflammation and chemoresistance in breast and colon cancer. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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14 pages, 3667 KiB

Open AccessArticle

Yadanziolide A Inhibits Proliferation and Induces Apoptosis of Hepatocellular Carcinoma via JAK-STAT Pathway: A Preclinical Study

by Lili Lin and Qi Chen

Biology 2024, 13(7), 528; https://doi.org/10.3390/biology13070528 - 16 Jul 2024

Viewed by 972

Abstract

Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. Yadanziolide A (Y-A), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver [...] Read more.

Liver cancer is a significant global health concern, prompting the search for innovative therapeutic solutions. Yadanziolide A (Y-A), a natural derivative of Brucea javanica, has emerged as a promising candidate for cancer treatment; however, its efficacy and underlying mechanisms in liver cancer remain incompletely understood. In this study, we conducted a comprehensive evaluation of Y-A’s effects on liver cancer cells using a range of in vitro assays and an orthotopic liver cancer mouse model. Our findings reveal that Y-A exerts dose-dependent cytotoxic effects on liver cancer cells, significantly inhibiting proliferation, migration, and invasion at concentrations ≥ 0.1 μM. Furthermore, Y-A induces apoptosis, as evidenced by increased apoptotic cell populations and apoptosome formation. In vivo studies confirm that Y-A inhibits tumor growth and reduces liver damage in mouse models. Mechanistically, Y-A targets the TNF-α/STAT3 pathway, inhibiting STAT3 and JAK2 phosphorylation, thereby activating apoptotic pathways and suppressing tumor cell growth. These results suggest that Y-A has promising anticancer activity and potential utility in liver cancer therapy. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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22 pages, 3527 KiB

Open AccessArticle

1,25-Dihydroxyvitamin D₃ Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line

by Jabril R. Johnson, Rachel N. Martini, Yate-Ching Yuan, Leanne Woods-Burnham, Mya Walker, Greisha L. Ortiz-Hernandez, Firas Kobeissy, Dorothy Galloway, Amani Gaddy, Chidinma Oguejiofor, Blake Allen, Deyana Lewis, Melissa B. Davis, K. Sean Kimbro, Clayton C. Yates, Adam B. Murphy and Rick A. Kittles

Biology 2024, 13(5), 346; https://doi.org/10.3390/biology13050346 - 15 May 2024

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Abstract

Vitamin D₃ is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D₃ deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling [...] Read more.

Vitamin D₃ is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D₃ deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D₃ metabolite, 1α,25(OH)₂D₃, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)₂D₃ treatment. Pathway enrichment analysis predicted 1α,25(OH)₂D_3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)₂D₃ treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)₂D₃ regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)₂D₃ could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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Review

Jump to: Research

17 pages, 1517 KiB

Open AccessReview

The Emerging Role of Ferroptosis in EBV-Associated Cancer: Implications for Cancer Therapy

by Shan He, Cheng Luo, Feng Shi, Jianhua Zhou and Li Shang

Biology 2024, 13(7), 543; https://doi.org/10.3390/biology13070543 - 18 Jul 2024

Viewed by 1227

Abstract

Ferroptosis is a novel and iron-dependent form of programmed cell death, which has been implicated in the pathogenesis of various human cancers. EBV is a well-recognized oncogenic virus that controls multiple signaling pathways within the host cell, including ferroptosis signaling. Recent studies show [...] Read more.

Ferroptosis is a novel and iron-dependent form of programmed cell death, which has been implicated in the pathogenesis of various human cancers. EBV is a well-recognized oncogenic virus that controls multiple signaling pathways within the host cell, including ferroptosis signaling. Recent studies show that inducing ferroptosis could be an efficient therapeutic strategy for EBV-associated tumors. This review will firstly describe the mechanism of ferroptosis, then summarize EBV infection and EBV-associated tumors, as well as the crosstalk between EBV infection and the ferroptosis signaling pathway, and finally discuss the role and potential application of ferroptosis-related reagents in EBV-associated tumors. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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22 pages, 2182 KiB

Open AccessReview

The Role of TRAIL Signaling in Cancer: Searching for New Therapeutic Strategies

by Cheng Luo, Shan He, Feng Shi, Jianhua Zhou and Li Shang

Biology 2024, 13(7), 521; https://doi.org/10.3390/biology13070521 - 15 Jul 2024

Viewed by 1547

Abstract

Cancer continues to pose a significant threat to global health, with its status as a leading cause of death remaining unchallenged. Within the realm of cancer research, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stands out as a critical player, having been identified [...] Read more.

Cancer continues to pose a significant threat to global health, with its status as a leading cause of death remaining unchallenged. Within the realm of cancer research, the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) stands out as a critical player, having been identified in the 1990s as the tenth member of the TNF family. This review examines the pivotal role of TRAIL in cancer biology, focusing on its ability to induce apoptosis in malignant cells through both endogenous and exogenous pathways. We provide an in-depth analysis of TRAIL’s intracellular signaling and intercellular communication, underscoring its potential as a selective anticancer agent. Additionally, the review explores TRAIL’s capacity to reshape the tumor microenvironment, thereby influencing cancer progression and response to therapy. With an eye towards future developments, we discuss the prospects of harnessing TRAIL’s capabilities for the creation of tailored, precision-based cancer treatments, aiming to enhance efficacy and improve patient survival rates. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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12 pages, 1319 KiB

Open AccessReview

Post-Translational Modifications (PTMs) of mutp53 and Epigenetic Changes Induced by mutp53

by Rossella Benedetti, Michele Di Crosta, Gabriella D’Orazi and Mara Cirone

Biology 2024, 13(7), 508; https://doi.org/10.3390/biology13070508 - 8 Jul 2024

Viewed by 1460

Abstract

Wild-type (wt) p53 and mutant forms (mutp53) play a key but opposite role in carcinogenesis. wtP53 acts as an oncosuppressor, preventing oncogenic transformation, while mutp53, which loses this property, may instead favor this process. This suggests that a better understanding of the mechanisms [...] Read more.

Wild-type (wt) p53 and mutant forms (mutp53) play a key but opposite role in carcinogenesis. wtP53 acts as an oncosuppressor, preventing oncogenic transformation, while mutp53, which loses this property, may instead favor this process. This suggests that a better understanding of the mechanisms activating wtp53 while inhibiting mutp53 may help to design more effective anti-cancer treatments. In this review, we examine possible PTMs with which both wt- and mutp53 can be decorated and discuss how their manipulation could represent a possible strategy to control the stability and function of these proteins, focusing in particular on mutp53. The impact of ubiquitination, phosphorylation, acetylation, and methylation of p53, in the context of several solid and hematologic cancers, will be discussed. Finally, we will describe some of the recent studies reporting that wt- and mutp53 may influence the expression and activity of enzymes responsible for epigenetic changes such as acetylation, methylation, and microRNA regulation and the possible consequences of such changes. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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18 pages, 2795 KiB

Open AccessReview

Drug Repurposing: Exploring Potential Anti-Cancer Strategies by Targeting Cancer Signalling Pathways

by Natalia Haddad, Sara Magura Gamaethige, Nadine Wehida and Ahmed Elbediwy

Biology 2024, 13(6), 386; https://doi.org/10.3390/biology13060386 - 28 May 2024

Viewed by 3076

Abstract

The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, [...] Read more.

The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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50 pages, 8349 KiB

Open AccessReview

Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression

by Yaxuan Zhou, Rinka Nakajima, Mashiro Shirasawa, Mariana Fikriyanti, Lin Zhao, Ritsuko Iwanaga, Andrew P. Bradford, Kenta Kurayoshi, Keigo Araki and Kiyoshi Ohtani

Biology 2023, 12(12), 1511; https://doi.org/10.3390/biology12121511 - 11 Dec 2023

Cited by 3 | Viewed by 4207

Abstract

The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. [...] Read more.

The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology. Full article

(This article belongs to the Special Issue Cancer and Signalling: Targeting Cellular Pathways)

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