International Journal of Molecular Sciences

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22 pages, 5283 KiB

Open AccessArticle

Understanding the Dosage-Dependent Role of Dicer1 in Thyroid Tumorigenesis

by María Rojo-Pardillo, Ludivine Godefroid, Geneviève Dom, Anne Lefort, Frederick Libert, Bernard Robaye and Carine Maenhaut

Int. J. Mol. Sci. 2024, 25(19), 10701; https://doi.org/10.3390/ijms251910701 - 4 Oct 2024

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Abstract

Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. Dicer1 has been found to [...] Read more.

Tumors originating from thyroid follicular cells are the most common endocrine tumors, with rising incidence. Despite a generally good prognosis, up to 20% of patients experience recurrence and persistence, highlighting the need to identify the underlying molecular mechanisms. Dicer1 has been found to be altered in papillary thyroid cancer (PTC). Studies suggest that Dicer1 functions as a haploinsufficient tumor suppressor gene: partial loss promotes tumorigenesis, while complete loss prevents it. To investigate the effects of partial or total Dicer1 loss in PTC in vitro, we generated stable Dicer1 (+/−) cell lines from TPC1 using CRISPR-Cas9, though no Dicer1 (−/−) lines could be produced. Therefore, siRNA against Dicer1 was transfected into Dicer1 (+/−) cell lines to further decrease its expression. Transcriptomic analysis revealed changes in proliferation and cell locomotion. BrdU staining indicated a slow-down of the cell cycle, with fewer cells in S phase and more in G0-G1-phase. Additionally, transwell assays showed decreased invasion and migration after Dicer1 knockdown by siRNA. Moreover, Dicer1 overexpression led to decreased proliferation, invasion, and increased apoptosis. Our findings deepen the understanding of Dicer1’s role in thyroid cancer, demonstrating that both complete elimination and overexpression of Dicer1 inhibit thyroid oncogenesis, highlighting Dicer1 as a promising target for novel therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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19 pages, 4219 KiB

Open AccessArticle

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation

by Tirzah Braz Petta and Joseph Carlson

Int. J. Mol. Sci. 2024, 25(19), 10427; https://doi.org/10.3390/ijms251910427 - 27 Sep 2024

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Abstract

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance [...] Read more.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis. In this study, we conducted a comprehensive analysis using publicly available datasets to elucidate the molecular mechanisms driving PARPi resistance in BRCA1-deficient ovarian cancer. Our findings reveal a central role for the interferon (IFN) pathway in mediating resistance in the context of BRCA1 deficiency. Through integrative bioinformatics approaches, we identified LY6E, an interferon-stimulated gene, as a key mediator of PARPi resistance, with its expression linked to an immunosuppressive tumor microenvironment (TME) encouraging tumor progression and invasion. LY6E amplification correlates with poor prognosis and increased expression of immune-related gene signatures, which is predictive of immunotherapy response. Interestingly, LY6E expression upon PARPi treatment resistance was found to be dependent on BRCA1 status. Gene expression analysis in the Orien/cBioPortal database revealed an association between LY6E and genes involved in DNA repair, such as Rad21 and PUF60, emphasizing the interplay between DNA repair pathways and immune modulation. Moreover, PUF60, Rad21, and LY6E are located on chromosome 8q24, a locus often amplified and associated with the progression of ovarian cancer. Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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16 pages, 1835 KiB

Open AccessArticle

Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Response to Bacillus Calmette–Guérin Immunotherapy in Bladder Cancer Patients

by Juwita N. Rahmat, Sin Mun Tham, Ting Li Ong, Yew Koon Lim, Mugdha Vijay Patwardhan, Lata Raman Nee Mani, Revathi Kamaraj, Yiong Huak Chan, Tsung Wen Chong, Edmund Chiong, Kesavan Esuvaranathan and Ratha Mahendran

Int. J. Mol. Sci. 2024, 25(16), 8947; https://doi.org/10.3390/ijms25168947 - 16 Aug 2024

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Abstract

Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 [...] Read more.

Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette–Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2B^FL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2B^Del/Del and 24.5% with GSTT2B^FL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2B^Del/Del and 53.8% of GSTT2B^FL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2B^Del/Del and 50% of GSTT2B^FL/FL. GSTT2^FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87–16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2B^Del/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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15 pages, 1784 KiB

Open AccessArticle

The Prognostic and Predictive Utility of CDX2 in Colorectal Cancer

by Wei Yen Chan, Wei Chua, Kate Wilkinson, Chandika Epitakaduwa, Hiren Mandaliya, Joseph Descallar, Tara Laurine Roberts, Therese Maria Becker, Weng Ng, Cheok Soon Lee and Stephanie Hui-Su Lim

Int. J. Mol. Sci. 2024, 25(16), 8673; https://doi.org/10.3390/ijms25168673 - 8 Aug 2024

Cited by 1 | Viewed by 1024

Abstract

Caudal type homeobox transcription factor 2 (CDX2) is a gastrointestinal cancer biomarker that regulates epithelial development and differentiation. Absence or low levels of CDX2 have been associated with poor prognosis and proposed as a chemotherapy response predictor. Tumour tissue samples from 668 patients [...] Read more.

Caudal type homeobox transcription factor 2 (CDX2) is a gastrointestinal cancer biomarker that regulates epithelial development and differentiation. Absence or low levels of CDX2 have been associated with poor prognosis and proposed as a chemotherapy response predictor. Tumour tissue samples from 668 patients with stage I–IV colorectal cancer were stained for CDX2 and stratified into two subgroups according to expression levels. Statistical tests were used to evaluate CDX2’s relationship with survival and chemotherapy response. Of 646 samples successfully stained, 51 (7.9%) had low CDX2 levels, and 595 (92.1%) had high levels. Low CDX2 staining was associated with poor differentiation and the presence of lymphovascular or perineural invasion and was more common in colon and right-sided tumours. Overall survival (p < 0.001) and disease-free survival (p = 0.009) were reduced in patients with low CDX2 expression. Multivariable analysis validated CDX2 as an independent poor prognostic factor after excluding confounding variables. There was no statistically significant improvement in survival with adjuvant chemotherapy in stage II colon cancer (p = 0.11). In the rectal cohort, there was no relationship between CDX2 levels and therapy response. While confirming the prognostic utility of CDX2 in colorectal cancer, our study highlights that larger studies are required to confirm its utility as a predictive chemotherapy biomarker, especially in left-sided and rectal cancers. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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19 pages, 3814 KiB

Open AccessArticle

Association of Inflammation and Immune Cell Infiltration with Estrogen Receptor Alpha in an Estrogen and Ionizing Radiation-Induced Breast Cancer Model

by Tania Koning and Gloria M. Calaf

Int. J. Mol. Sci. 2024, 25(16), 8604; https://doi.org/10.3390/ijms25168604 - 7 Aug 2024

Cited by 1 | Viewed by 854

Abstract

Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to [...] Read more.

Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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15 pages, 3564 KiB

Open AccessArticle

Anti-HER2 Cancer-Specific mAb, H₂Mab-250-hG₁, Possesses Higher Complement-Dependent Cytotoxicity than Trastuzumab

by Hiroyuki Suzuki, Tomokazu Ohishi, Tomohiro Tanaka, Mika K. Kaneko and Yukinari Kato

Int. J. Mol. Sci. 2024, 25(15), 8386; https://doi.org/10.3390/ijms25158386 - 1 Aug 2024

Cited by 1 | Viewed by 1270

Abstract

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H₂Mab-250/H₂CasMab-2. In flow [...] Read more.

Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H₂Mab-250/H₂CasMab-2. In flow cytometry and immunohistochemistry, H₂Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG₁ version of H₂Mab-250 (H₂Mab-250-hG₁) possesses compatible in vivo antitumor effects against breast cancer xenografts to trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H₂Mab-250-hG₁ and trastuzumab. Both H₂Mab-250-hG₁ and trastuzumab showed ADCC activity against HER2-overexpressed Chinese hamster ovary -K1 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed where trastuzumab showed a more significant ADCC effect compared to H₂Mab-250-hG₁. Importantly, H₂Mab-250-hG₁ exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in the mouse IgG_2a types of both H₂Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H₂Mab-250-hG₁ and trastuzumab, and indicate a future direction for the clinical development of H₂Mab-250-hG₁ against HER2-positive tumors. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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11 pages, 1262 KiB

Open AccessArticle

Analysis of Expression of the ANG1, CaSR and FAK Proteins in Uterine Fibroids

by Anna Markowska, Mateusz de Mezer, Paweł Kurzawa, Wiesława Bednarek, Anna Gryboś, Monika Krzyżaniak, Janina Markowska, Marian Gryboś and Jakub Żurawski

Int. J. Mol. Sci. 2024, 25(13), 7164; https://doi.org/10.3390/ijms25137164 - 28 Jun 2024

Viewed by 1006

Abstract

Understanding the molecular factors involved in the development of uterine myomas may result in the use of pharmacological drugs instead of aggressive surgical treatment. ANG1, CaSR, and FAK were examined in myoma and peripheral tissue samples taken from women after myoma surgery and [...] Read more.

Understanding the molecular factors involved in the development of uterine myomas may result in the use of pharmacological drugs instead of aggressive surgical treatment. ANG1, CaSR, and FAK were examined in myoma and peripheral tissue samples taken from women after myoma surgery and in normal uterine muscle tissue samples taken from the control group. Tests were performed using tissue microarray immunohistochemistry. No statistically significant differences in ANG1 expression between the tissue of the myoma, the periphery, and the normal uterine muscle tissue of the control group were recorded. The CaSR value was reduced in the myoma and peripheral tissue and normal in the group of women without myomas. FAK expression was also lower in the myoma and periphery compared to the healthy uterine myometrium. Calcium supplementation could have an effect on stopping the growth of myomas. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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9 pages, 875 KiB

Open AccessCommunication

Immunohistochemical Expression of Human Epidermal Growth Factor Receptor 2 and Ki67 in Apocrine Gland Anal Sac Adenocarcinoma

by Felipe Paiva, Júlio Santos, Gabriel Carra, Felipe Sueiro, Paulo Jark and Andrigo Nardi

Int. J. Mol. Sci. 2024, 25(12), 6451; https://doi.org/10.3390/ijms25126451 - 12 Jun 2024

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Abstract

Apocrine gland anal sac adenocarcinoma is an aggressive neoplasm, and surgery remains the treatment of choice, although it is controversial in advanced cases. The prognostic factors are not well established. Human Epidermal Growth Factor Receptor 2 (HER2) is a membrane protein related to [...] Read more.

Apocrine gland anal sac adenocarcinoma is an aggressive neoplasm, and surgery remains the treatment of choice, although it is controversial in advanced cases. The prognostic factors are not well established. Human Epidermal Growth Factor Receptor 2 (HER2) is a membrane protein related to tumorigenesis, whereas Ki67 is a nuclear protein related to cell proliferation. Both are potential prognostic markers and therapeutic targets. This study aimed to evaluate the expression of HER2 and Ki67 markers in canine apocrine gland anal sac adenocarcinoma. The tumor samples were divided into four groups: largest tumor diameter less than 2.5 cm, largest tumor diameter greater than 2.5 cm, metastatic lymph nodes, and control group of non-neoplastic anal sacs. Each contained 10 samples. Immunohistochemistry was performed to verify the expression of HER2 and Ki67 markers. Positive HER2 staining was observed in 45% of the neoplastic cases and negative HER2 staining in 100% of the control group. The Ki67 expression had a median of 25% in all groups, except for the control group, which had a median of 8%. The HER2 and Ki67 expression was present in apocrine gland anal sac adenocarcinoma, making them potential therapeutic targets. However, it was not possible to determine the clinical value of either marker. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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17 pages, 3917 KiB

Open AccessArticle

Prognostic Value of HHLA2 in Patients with Solid Tumors: A Meta-Analysis

by Agnieszka Kula, Miriam Dawidowicz, Sylwia Mielcarska, Elżbieta Świętochowska and Dariusz Waniczek

Int. J. Mol. Sci. 2024, 25(9), 4760; https://doi.org/10.3390/ijms25094760 - 26 Apr 2024

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Abstract

HHLA2 is a checkpoint from the B7 family that can play a co-stimulatory or co-inhibitory role in cancer, depending on the binding receptor. The aim of this meta-analysis was to assess the relationship between HHLA2 levels and its impact on the prognosis of [...] Read more.

HHLA2 is a checkpoint from the B7 family that can play a co-stimulatory or co-inhibitory role in cancer, depending on the binding receptor. The aim of this meta-analysis was to assess the relationship between HHLA2 levels and its impact on the prognosis of patients with solid cancers. The study used data from PubMed, Embase, Web of Science (WOS), Cochrane and SCOPUS databases. The R studio software was used for the data analysis. The study assessed overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), recurrence-free survival (RFS), and disease-free survival (DFS) by pooling appropriate hazard ratios (HR). Eighteen studies (2880 patients’ data) were included. High expression of HHLA2 was associated with worse OS (HR = 1.58, 95% CI: 1.23–2.03), shorter RFS (HR = 1.95, 95% CI: 1.38–2.77) and worse DFS (HR = 1.45, 95% CI: 1.01–2.09) in patients with solid cancers. The current study suggests that high expression of HHLA2 is associated with poorer prognosis in patients with solid cancers. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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16 pages, 7244 KiB

Open AccessArticle

Lung Cancer Cell-Derived Exosome Detection Using Electrochemical Approach towards Early Cancer Screening

by Koosha Irani, Hossein Siampour, Abdollah Allahverdi, Ahmad Moshaii and Hossein Naderi-Manesh

Int. J. Mol. Sci. 2023, 24(24), 17225; https://doi.org/10.3390/ijms242417225 - 7 Dec 2023

Cited by 1 | Viewed by 1885

Abstract

Lung cancer is one of the deadliest cancers worldwide due to the inability of existing methods for early diagnosis. Tumor-derived exosomes are nano-scale vesicles released from tumor cells to the extracellular environment, and their investigation can be very useful in both biomarkers for [...] Read more.

Lung cancer is one of the deadliest cancers worldwide due to the inability of existing methods for early diagnosis. Tumor-derived exosomes are nano-scale vesicles released from tumor cells to the extracellular environment, and their investigation can be very useful in both biomarkers for early cancer screening and treatment assessment. This research detected the exosomes via an ultrasensitive electrochemical biosensor containing gold nano-islands (Au-NIs) structures. This way, a high surface-area-to-volume ratio of nanostructures was embellished on the FTO electrodes to increase the chance of immobilizing the CD-151 antibody. In this way, a layer of gold was first deposited on the electrode by physical vapor deposition (PVD), followed by thermal annealing to construct primary gold seeds on the surface of the electrode. Then, gold seeds were grown by electrochemical deposition through gold salt. The cell-derived exosomes were successfully immobilized on the FTO electrode through the CD-151 antibody, and cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) methods were used in this research. In the CV method, the change in the current passing through the working electrode is measured so that the connection of exosomes causes the current to decrease. In the EIS method, surface resistance changes were investigated so that the binding of exosomes increased the surface resistance. Various concentrations of exosomes in both cell culture and blood serum samples were measured to test the sensitivity of the biosensor, which makes our biosensor capable of detecting 20 exosomes per milliliter. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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22 pages, 2662 KiB

Open AccessArticle

miRNAs in the Box: Potential Diagnostic Role for Extracellular Vesicle-Packaged miRNA-27a and miRNA-128 in Breast Cancer

by Cinzia Giordano, Felice Maria Accattatis, Luca Gelsomino, Piercarlo Del Console, Balázs Győrffy, Mario Giuliano, Bianca Maria Veneziani, Grazia Arpino, Carmine De Angelis, Pietro De Placido, Erica Pietroluongo, Francesco Zinno, Daniela Bonofiglio, Sebastiano Andò, Ines Barone and Stefania Catalano

Int. J. Mol. Sci. 2023, 24(21), 15695; https://doi.org/10.3390/ijms242115695 - 28 Oct 2023

Cited by 3 | Viewed by 2178

Abstract

Circulating extracellular vesicle (EV)-derived microRNAs (miRNAs) are now considered the next generation of cancer “theranostic” tools, with strong clinical relevance. Although their potential in breast cancer diagnosis has been widely reported, further studies are still required to address this challenging issue. The present [...] Read more.

Circulating extracellular vesicle (EV)-derived microRNAs (miRNAs) are now considered the next generation of cancer “theranostic” tools, with strong clinical relevance. Although their potential in breast cancer diagnosis has been widely reported, further studies are still required to address this challenging issue. The present study examined the expression profiles of EV-packaged miRNAs to identify novel miRNA signatures in breast cancer and verified their diagnostic accuracy. Circulating EVs were isolated from healthy controls and breast cancer patients and characterized following the MISEV 2018 guidelines. RNA-sequencing and real-time PCR showed that miRNA-27a and miRNA-128 were significantly down-regulated in patient-derived EVs compared to controls in screening and validation cohorts. Bioinformatics analyses of miRNA-target genes indicated several enriched biological processes/pathways related to breast cancer. Receiver operating characteristic (ROC) curves highlighted the ability of these EV-miRNAs to distinguish breast cancer patients from non-cancer controls. According to other reports, the levels of EV-miRNA-27a and EV-miRNA-128 are not associated with their circulating ones. Finally, evidence from the studies included in our systematic review underscores how the expression of these miRNAs in biofluids is still underinvestigated. Our findings unraveled the role of serum EV-derived miRNA-27a and miRNA-128 in breast cancer, encouraging further investigation of these two miRNAs within EVs towards improved breast cancer detection. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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Review

Jump to: Research

21 pages, 4561 KiB

Open AccessReview

The Estrogen–Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection

by Ying Zhao, Daniel J. Klionsky, Xin Wang, Qiaoying Huang, Zixin Deng and Jin Xiang

Int. J. Mol. Sci. 2024, 25(23), 12576; https://doi.org/10.3390/ijms252312576 - 22 Nov 2024

Abstract

Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet [...] Read more.

Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet to reach a consensus on the most effective approach to manipulating autophagy, with ongoing debates about whether its inhibition or stimulation is preferable for managing these complex conditions. One critical factor contributing to the variability in treatment responses for both cancers and infectious diseases is estrogen, a hormone known for its diverse biological effects. Given the strong correlations observed between estrogen signaling and autophagy, this review seeks to summarize the intricate molecular mechanisms that underlie the dual cytoprotective effects of estrogen signaling in conjunction with autophagy. We highlight recent findings from studies that involve various ligands, disease contexts, and cell types, including immune cells. Furthermore, we discuss several factors that regulate autophagy in the context of estrogen’s influence. Ultimately, we propose a hypothetical model to elucidate the regulatory effects of the estrogen–autophagy axis on cell fate. Understanding these interactions is crucial for advancing our knowledge of related diseases and facilitating the development of innovative treatment strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

18 pages, 1799 KiB

Open AccessReview

Mechanisms Behind the Impact of PIWI Proteins on Cancer Cells: Literature Review

by Piotr Limanówka, Błażej Ochman and Elżbieta Świętochowska

Int. J. Mol. Sci. 2024, 25(22), 12217; https://doi.org/10.3390/ijms252212217 - 14 Nov 2024

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Abstract

The P-Element-induced wimpy testis (PIWI) group of proteins plays a key role in RNA interference, particularly in the regulation of small non-coding RNAs. However, in recent years, PIWIs have gained attention in several diseases, mainly cancer. Therefore, the aim of this review was [...] Read more.

The P-Element-induced wimpy testis (PIWI) group of proteins plays a key role in RNA interference, particularly in the regulation of small non-coding RNAs. However, in recent years, PIWIs have gained attention in several diseases, mainly cancer. Therefore, the aim of this review was to evaluate current knowledge about the impact of PIWI proteins on cancer cells. PIWIs alter a number of pathways within cells, resulting in significant changes in cell behavior. Basic processes of cancer cells have been shown to be altered by either overexpression or inhibition of PIWIs. Regulation of apoptosis, metastasis, invasion, or proliferation of cancerous cells by these proteins proves their involvement in the progression of the malignancy. It has been revealed that PIWIs are also connected with cancer stem cells (CSCs), which proves their ability to become a therapeutic target. However, research on this topic is still fairly limited, and with significant differences between cancer types, it is necessary to refrain from making any decisive conclusions. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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20 pages, 1007 KiB

Open AccessReview

Biomarkers in Colorectal Cancer: Actual and Future Perspectives

by Horia-Dan Lișcu, Nicolae Verga, Dimitrie-Ionuț Atasiei, Dumitru-Cristinel Badiu, Adrian Vasile Dumitru, Flavia Ultimescu, Christopher Pavel, Roxana-Elena Stefan, Diandra-Carmen Manole and Andreea-Iuliana Ionescu

Int. J. Mol. Sci. 2024, 25(21), 11535; https://doi.org/10.3390/ijms252111535 - 27 Oct 2024

Viewed by 1092

Abstract

Biomarkers in colorectal cancer (CRC) are of great interest in the current literature due to improvements in techniques such as liquid biopsy and next-generation sequencing (NGS). However, screening methods vary globally, with multi-target stool DNA (mt-sDNA) predominantly used in the USA and, more [...] Read more.

Biomarkers in colorectal cancer (CRC) are of great interest in the current literature due to improvements in techniques such as liquid biopsy and next-generation sequencing (NGS). However, screening methods vary globally, with multi-target stool DNA (mt-sDNA) predominantly used in the USA and, more recently, the Cologuard Plus; biomarkers such as the Galectins family and septins show promise in early detection. Gut microbiome assessments, such as Fusobacterium nucleatum, are under intense exploration. Diagnostic tests, such as circulating DNA analysis via NGS, exhibit effectiveness and are being increasingly adopted. Circulating tumor cells emerge as potential alternatives to traditional methods in terms of diagnosis and prognosis. Predictive biomarkers are well established in guidelines; nonetheless, with the aid of machine learning and artificial intelligence, these biomarkers may be improved. This review critically explores the actual dynamic landscape of CRC biomarkers and future, promising biomarkers involved in screening, diagnosis, and prognosis. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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15 pages, 1364 KiB

Open AccessReview

Circular RNAs: Novel Players in Cancer Mechanisms and Therapeutic Strategies

by Jimi Kim

Int. J. Mol. Sci. 2024, 25(18), 10121; https://doi.org/10.3390/ijms251810121 - 20 Sep 2024

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Abstract

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have emerged as pivotal players in gene regulation. Our understanding of circRNAs has greatly expanded over the last decade, with studies elucidating their biology and exploring their therapeutic applications. In this review, [...] Read more.

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have emerged as pivotal players in gene regulation. Our understanding of circRNAs has greatly expanded over the last decade, with studies elucidating their biology and exploring their therapeutic applications. In this review, we provide an overview of the current understanding of circRNA biogenesis, outline their mechanisms of action in cancer, and assess their clinical potential as biomarkers. Furthermore, we discuss circRNAs as a potential therapeutic strategy, including recent advances in circRNA production and translation, along with proof-of-concept preclinical studies of cancer vaccines. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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23 pages, 2244 KiB

Open AccessReview

Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies

by Edoardo Agosti, Sara Antonietti, Tamara Ius, Marco Maria Fontanella, Marco Zeppieri and Pier Paolo Panciani

Int. J. Mol. Sci. 2024, 25(14), 7979; https://doi.org/10.3390/ijms25147979 - 22 Jul 2024

Cited by 2 | Viewed by 1881

Abstract

Gliomas’ aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma [...] Read more.

Gliomas’ aggressive nature and resistance to therapy make them a major problem in oncology. Gliomas continue to have dismal prognoses despite significant advancements in medical science, and traditional treatments like surgery, radiation (RT), and chemotherapy (CT) frequently prove to be ineffective. After glioma stem cells (GSCs) were discovered, the traditional view of gliomas as homogeneous masses changed. GSCs are essential for tumor growth, treatment resistance, and recurrence. These cells’ distinct capacities for differentiation and self-renewal are changing our knowledge of the biology of gliomas. This systematic literature review aims to uncover the molecular mechanisms driving glioma progression associated with GSCs. The systematic review adhered to PRISMA guidelines, with a thorough literature search conducted on PubMed, Ovid MED-LINE, and Ovid EMBASE. The first literature search was performed on 1 March 2024, and the search was updated on 15 May 2024. Employing MeSH terms and Boolean operators, the search focused on molecular mechanisms associated with GCSs-mediated glioma progression. Inclusion criteria encompassed English language studies, preclinical studies, and clinical trials. A number of 957 papers were initially identified, of which 65 studies spanning from 2005 to 2024 were finally included in the review. The main GSC model distribution is arranged in decreasing order of frequency: U87: 20 studies (32.0%); U251: 13 studies (20.0%); A172: 4 studies (6.2%); and T98G: 2 studies (3.17%). From most to least frequent, the distribution of the primary GSC pathway is as follows: Notch: 8 studies (12.3%); STAT3: 6 studies (9.2%); Wnt/β-catenin: 6 studies (9.2%); HIF: 5 studies (7.7%); and PI3K/AKT: 4 studies (6.2%). The distribution of molecular effects, from most to least common, is as follows: inhibition of differentiation: 22 studies (33.8%); increased proliferation: 18 studies (27.7%); enhanced invasive ability: 15 studies (23.1%); increased self-renewal: 5 studies (7.7%); and inhibition of apoptosis: 3 studies (4.6%). This work highlights GSC heterogeneity and the dynamic interplay within the glioblastoma microenvironment, underscoring the need for a tailored approach. A few key pathways influencing GSC behavior are JAK/STAT3, PI3K/AKT, Wnt/β-catenin, and Notch. Therapy may target these pathways. This research urges more study to fill in knowledge gaps in the biology of GSCs and translate findings into useful treatment approaches that could improve GBM patient outcomes. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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Open AccessReview

Glioblastoma Immunotherapy: A Systematic Review of the Present Strategies and Prospects for Advancements

by Edoardo Agosti, Marco Zeppieri, Lucio De Maria, Camilla Tedeschi, Marco Maria Fontanella, Pier Paolo Panciani and Tamara Ius

Int. J. Mol. Sci. 2023, 24(20), 15037; https://doi.org/10.3390/ijms242015037 - 10 Oct 2023

Cited by 21 | Viewed by 5554

Abstract

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess [...] Read more.

Glioblastoma (GBM) is characterized by aggressive growth and high rates of recurrence. Despite the advancements in conventional therapies, the prognosis for GBM patients remains poor. Immunotherapy has recently emerged as a potential treatment option. The aim of this systematic review is to assess the current strategies and future perspectives of the GBM immunotherapy strategies. A systematic search was conducted across major medical databases (PubMed, Embase, and Cochrane Library) up to 3 September 2023. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to “glioblastomas,” “immunotherapies,” and “treatment.” The studies included in this review consist of randomized controlled trials, non-randomized controlled trials, and cohort studies reporting on the use of immunotherapies for the treatment of gliomas in human subjects. A total of 1588 papers are initially identified. Eligibility is confirmed for 752 articles, while 655 are excluded for various reasons, including irrelevance to the research topic (627), insufficient method and results details (12), and being case-series or cohort studies (22), systematic literature reviews, or meta-analyses (3). All the studies within the systematic review were clinical trials spanning from 1995 to 2023, involving 6383 patients. Neuro-oncology published the most glioma immunotherapy-related clinical trials (15/97, 16%). Most studies were released between 2018 and 2022, averaging nine publications annually during this period. Adoptive cellular transfer chimeric antigen receptor (CAR) T cells were the primary focus in 11% of the studies, with immune checkpoint inhibitors (ICIs), oncolytic viruses (OVs), and cancer vaccines (CVs) comprising 26%, 12%, and 51%, respectively. Phase-I trials constituted the majority at 51%, while phase-III trials were only 7% of the total. Among these trials, 60% were single arm, 39% double arm, and one multi-arm. Immunotherapies were predominantly employed for recurrent GBM (55%). The review also revealed ongoing clinical trials, including 9 on ICIs, 7 on CVs, 10 on OVs, and 8 on CAR T cells, totaling 34 trials, with phase-I trials representing the majority at 53%, and only one in phase III. Overcoming immunotolerance, stimulating robust tumor antigen responses, and countering immunosuppressive microenvironment mechanisms are critical for curative GBM immunotherapy. Immune checkpoint inhibitors, such as PD-1 and CTLA-4 inhibitors, show promise, with the ongoing research aiming to enhance their effectiveness. Personalized cancer vaccines, especially targeting neoantigens, offer substantial potential. Oncolytic viruses exhibited dual mechanisms and a breakthrough status in the clinical trials. CAR T-cell therapy, engineered for specific antigen targeting, yields encouraging results, particularly against IL13 Rα2 and EGFRvIII. The development of second-generation CAR T cells with improved specificity exemplifies their adaptability. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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15 pages, 999 KiB

Open AccessReview

Prostate Cancer Stem Cells: Biology and Treatment Implications

by Ioannis M. Koukourakis, Kalliopi Platoni, Vassilis Kouloulias, Stella Arelaki and Anna Zygogianni

Int. J. Mol. Sci. 2023, 24(19), 14890; https://doi.org/10.3390/ijms241914890 - 4 Oct 2023

Cited by 6 | Viewed by 2817

Abstract

Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas [...] Read more.

Stem cells differentiate into mature organ/tissue-specific cells at a steady pace under normal conditions, but their growth can be accelerated during the process of tissue healing or in the context of certain diseases. It is postulated that the proliferation and growth of carcinomas are sustained by the presence of a vital cellular compartment resembling stem cells residing in normal tissues: ‘stem-like cancer cells’ or cancer stem cells (CSCs). Mutations in prostate stem cells can lead to the formation of prostate cancer. Prostate CSCs (PCSCs) have been identified and partially characterized. These express surface markers include CD44, CD133, integrin α2β1, and pluripotency factors like OCT4, NANOG, and SOX2. Several signaling pathways are also over-activated, including Notch, PTEN/Akt/PI3K, RAS-RAF-MEK-ERK and HH. Moreover, PCSCs appear to induce resistance to radiotherapy and chemotherapy, while their presence has been linked to aggressive cancer behavior and higher relapse rates. The development of treatment policies to target PCSCs in tumors is appealing as radiotherapy and chemotherapy, through cancer cell killing, trigger tumor repopulation via activated stem cells. Thus, blocking this reactive stem cell mobilization may facilitate a positive outcome through cytotoxic treatment. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

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