Journal of Molecular Pathology

16 pages, 1316 KB

Open AccessArticle

Prevalence and Clinical Significance of miR-155-5p and miR-221-3p in Colorectal and Thyroid Cancer: A Study in Sulaymaniyah Province

by Hersh Abdul Ham-Karim

J. Mol. Pathol. 2025, 6(4), 33; https://doi.org/10.3390/jmp6040033 - 18 Dec 2025

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Abstract

Background: MicroRNAs (miRNAs) such as miR-155-5p and miR-221-3p are key regulators of gene expression in cancer. Although both have been implicated in colorectal cancer (CRC) and papillary thyroid carcinoma (PTC), data on their regional expression profiles and clinical associations remain scarce, particularly in [...] Read more.

Background: MicroRNAs (miRNAs) such as miR-155-5p and miR-221-3p are key regulators of gene expression in cancer. Although both have been implicated in colorectal cancer (CRC) and papillary thyroid carcinoma (PTC), data on their regional expression profiles and clinical associations remain scarce, particularly in the Middle East. This study assessed the expression patterns and clinical relevance of miR-155-5p and miR-221-3p in CRC and PTC patients from Sulaymaniyah Province, Iraq. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and adjacent normal tissue samples were collected from 60 CRC patients and 50 PTC patients. miRNA expression levels were quantified using real-time quantitative PCR (RT-qPCR) and analyzed by the ΔΔCt method, adjusted for tumor cellularity. Statistical analyses were conducted to evaluate associations between miRNA expression and clinicopathological parameters. Results: miR-155-5p and miR-221-3p were frequently overexpressed in both CRC (65%) and PTC (72% and 68%, respectively). In CRC, miR-155-5p expression correlated significantly with histological grade, tumor location, and TNM stage (p < 0.05), while miR-221-3p did not show significant associations with clinicopathological features. In PTC, miR-155-5p exhibited a trend toward association with TNM stage (p = 0.02). No significant differences in expression levels of these miRNAs were observed between CRC and PTC samples. Conclusions: Overall, miR-155-5p and miR-221-3p are consistently overexpressed in CRC and PTC, indicating their potential as diagnostic biomarkers. miR-155-5p, in particular, shows promise as a marker of disease progression in CRC. These findings underscore the importance of region-specific studies in advancing our understanding of the molecular landscape of cancer. Full article

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30 pages, 1235 KB

Open AccessReview

Molecular Perspective on Proteases: Regulation of Programmed Cell Death Signaling, Inflammation and Pathological Outcomes

by Aafreen Ansari, Kishu Ranjan, Ashish Kumar and Chandramani Pathak

J. Mol. Pathol. 2025, 6(4), 32; https://doi.org/10.3390/jmp6040032 - 12 Dec 2025

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Abstract

Proteases are essential enzymes that regulate numerous physiological processes and cellular signaling networks to maintain homeostasis and cellular fate. This regulation is mediated by a group of proteases with the primary function of cleaving peptide bonds, thereby modulating the activity of proteins for [...] Read more.

Proteases are essential enzymes that regulate numerous physiological processes and cellular signaling networks to maintain homeostasis and cellular fate. This regulation is mediated by a group of proteases with the primary function of cleaving peptide bonds, thereby modulating the activity of proteins for vital functions and influencing various cellular and physiological functions including digestion, absorption, cellular signaling, apoptosis, inflammation, immune response, cell growth, differentiation, cell death, and reproduction. Proteases define the fate of cells by modulating the downstream signal transduction pathways for modalities of cell death known as apoptosis, necroptosis, pyroptosis, and autophagy. Similarly, during inflammatory stimulation, proteases orchestrate a cascade of pathways that optimize the immune response to pathogens. Proteases play a crucial role in the pathogenesis of various human diseases, including cancer, metabolic, inflammatory, and neurological disorders. The activation of specific proteases determines the outcomes of different forms of cell death inflammation and imbalance may cause various pathological manifestations highlighted in this review. Understanding protease-mediated signaling mechanisms is therefore vital for elucidating disease pathogenesis and identifying potential therapeutic targets. Full article

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14 pages, 830 KB

Open AccessReview

Cancer-Associated Fibroblasts and Epithelial–Mesenchymal Transition as Critical Contributors to Renal Cell Carcinoma Progression

by Sergii Vernygorodskyi, Anton B. Tonchev, Nikolai T. Evtimov and Kameliya Zhechkova Bratoeva

J. Mol. Pathol. 2025, 6(4), 31; https://doi.org/10.3390/jmp6040031 - 9 Dec 2025

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Abstract

Renal cell carcinoma (RCC) features a complex tumor microenvironment, where cancer-associated fibroblasts (CAFs) play key roles in tumor progression, epithelial–mesenchymal transition (EMT), immune evasion, and resistance to treatment. This article updates our understanding of CAF origins, diversity, and functions in RCC, incorporating recent [...] Read more.

Renal cell carcinoma (RCC) features a complex tumor microenvironment, where cancer-associated fibroblasts (CAFs) play key roles in tumor progression, epithelial–mesenchymal transition (EMT), immune evasion, and resistance to treatment. This article updates our understanding of CAF origins, diversity, and functions in RCC, incorporating recent single-cell RNA sequencing (scRNA-seq) data that refine CAF subtypes. The paper explores the mechanistic interactions between CAFs and EMT, focusing on CAF-derived signaling pathways like TGF-β, IL-6/STAT3, HGF/c-MET, and Wnt/β-catenin, as well as extracellular-vesicle-mediated transfer of miRNAs and lncRNAs that promote metastatic behavior in RCC. It also addresses how CAF-driven remodeling of the extracellular matrix, metabolic changes, and activation of YAP/TAZ contribute to invasion and resistance to therapies, particularly in relation to tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint blockade. The review highlights emerging therapeutic strategies targeting CAFs, such as inhibiting specific signaling pathways, disrupting CAF–tumor cell communication, and selectively depleting CAFs. In conclusion, it identifies limitations in current CAF classification systems and proposes future research avenues to improve RCC-specific CAF profiling and exploit the CAF–EMT axis for therapeutic gain. Full article

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17 pages, 1004 KB

Open AccessArticle

Incorporation of Microsatellite Instability and Tumor-Infiltrating Lymphocytes in Opisthorchis viverrini-Associated Cholangiocarcinoma: Predicting Patient Outcomes

by Natcha Khuntikeo, Apiwat Jareanrat, Vasin Thanasukarn, Tharatip Srisuk, Vor Luvira, Watcharin Loilome, Poramate Klanrit, Anchalee Techasen, Jarin Chindaprasirt, Prakasit Sa-Ngiamwibool, Chaiwat Aphivatanasiri, Sureerat Padthaisong, Piya Prajumwongs and Attapol Titapun

J. Mol. Pathol. 2025, 6(4), 30; https://doi.org/10.3390/jmp6040030 - 1 Dec 2025

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Abstract

Background: Cholangiocarcinoma (CCA) has the highest incidence in Northeastern Thailand, where patients generally present with late diagnosis and poor prognosis. Opisthorchis viverrini (OV) infection is the major cause of CCA, with oxidative stress driving DNA mutations and genetic instability. Microsatellite instability (MSI) is [...] Read more.

Background: Cholangiocarcinoma (CCA) has the highest incidence in Northeastern Thailand, where patients generally present with late diagnosis and poor prognosis. Opisthorchis viverrini (OV) infection is the major cause of CCA, with oxidative stress driving DNA mutations and genetic instability. Microsatellite instability (MSI) is a predictive biomarker in several cancers. This study aimed to investigate MSI status and its association with clinicopathological features and survival of CCA patients. Methods: Tissue and serum samples were collected from 25 surgical CCA patients. MSI status and mismatch repair (MMR) proteins were evaluated using an MSI scanner and immunohistochemistry (IHC). Serum OV IgG was assessed by ELISA, while tumor-infiltrating lymphocytes (TILs) were evaluated by two pathologists. Associations of MSI with clinicopathological features, OV status, MMR, and survival were analyzed. Results: Among CCA patients, 66.7% were MSI-high and 33.3% were MSI-low. MSI-high significantly correlated with age < 57 years, intraductal growth pattern, OV positivity, and early-stage disease. Patients with MSI-high and high TILs showed markedly improved median survival compared to MSI-low with low TILs (94.0 vs. 16.8 and 3.0 months; HR = 6.82 and 14.10; p = 0.004 and 0.001). Incorporation of MSI and TILs remained an independent prognostic factor in multivariate analysis (p < 0.05). Conclusions: MSI-high is highly prevalent in OV-associated CCA and is associated with intraductal growth, OV infection, and early-stage disease. Combined MSI and TIL status may serve as an independent prognostic factor, warranting validation in larger cohorts. Full article

(This article belongs to the Special Issue Advancing Cancer Diagnosis: Integrating Molecular Pathology into Histopathology for Solid Tumors)

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11 pages, 1328 KB

Open AccessCommentary

Mpox Insights: From Structure to Human Cell Interaction

by Md S. Zaman, Robert C. Sizemore, Draven Rodriguez, Emilio Lopez, S. M. Golam Alam, Suleyman Tufa, Juan C. Lopez-Alvarenga, Nuraly S. Akimbekov and Mohammed S. Razzaque

J. Mol. Pathol. 2025, 6(4), 29; https://doi.org/10.3390/jmp6040029 - 21 Nov 2025

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Abstract

Mpox, a zoonotic viral disease, has emerged as a global concern due to outbreaks in both endemic and non-endemic regions in 2022. Rodents, including African squirrels and Gambian pouched rats, are suspected key reservoirs, with human infections occurring through direct contact with infected [...] Read more.

Mpox, a zoonotic viral disease, has emerged as a global concern due to outbreaks in both endemic and non-endemic regions in 2022. Rodents, including African squirrels and Gambian pouched rats, are suspected key reservoirs, with human infections occurring through direct contact with infected animals or bushmeat consumption. Previously confined to rural Africa, mpox has spread via international travel and the exotic pet trade. Human-to-human transmission occurs mainly via respiratory droplets and direct contact with bodily fluids or lesions. The virus has a double-stranded DNA genome within a lipid envelope. Despite lower mutation rates in DNA viruses, mpox has developed mutations, particularly in genes like F8L, G9R, and F13L, facilitating viral replication and immune evasion. The virus targets immune cells such as monocytes and macrophages, weakening host defenses and prolonging infection. Immunocompromised individuals are at higher risk of severe complications. Although generally self-limiting, severe cases may require antiviral treatment. This article briefly summarizes the therapeutic and preventive strategies, and public health measures to combat zoonotic threats. Full article

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15 pages, 3469 KB

Open AccessCommunication

STK11 Mutated Lung Adenocarcinoma: A Molecular and Clinicopathologic Study

by Jeffrey Jean, William D. Wallace and Guang-Qian Xiao

J. Mol. Pathol. 2025, 6(4), 28; https://doi.org/10.3390/jmp6040028 - 17 Nov 2025

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Abstract

Targetable gene alterations have become increasingly important in the treatment of cancers. Thirty STK11-mutated lung cancers from 199 cases with molecular profiling performed during 2016–2024 were studied for clinical, morphologic, immunohistochemical (IHC) and molecular features. Of the 30 STK11-mutated lung cancers, [...] Read more.

Targetable gene alterations have become increasingly important in the treatment of cancers. Thirty STK11-mutated lung cancers from 199 cases with molecular profiling performed during 2016–2024 were studied for clinical, morphologic, immunohistochemical (IHC) and molecular features. Of the 30 STK11-mutated lung cancers, 29 were lung adenocarcinomas (LADCs) and 1 was large cell neuroendocrine carcinoma (LCNEC). STK11 mutation was not found in other subtypes of lung cancers. Of the 29 STK11-mutated LADCs, 6 (21%) were mucinous and 23 (79%) were non-mucinous. Of the 19 non-mucinous LADCs with sufficient material for IHC, 9 (47%) displayed acinar/papillary/lepidic patterns, 8 (42%) were poorly differentiated (solid/trabecular/basaloid/complex glandular), and 2 (11%) had mixed solid and acinar patterns. The most common concurrent altered genes were KRAS (52%), followed by TP53 (38%), KEAP1 (34%), and DNA repair genes (BRCA2/ATM) (21%). A total of 6/15 (40%) LADCs with a KRAS mutation presented with mucinous morphology. Concurrent EGFR, ROS, or ALK alterations with STK11 mutation were rare or non-existent. Of the 3 LADCs with SMARCA4 deficiency, 2 were mucinous and 1 had basaloid/adenoid cystic-like features. All the cases were microsatellite stable (MSS). The majority (55%) had low TMB (<10). Most (86%) had PD-L1 TPS 0 or <5%. Among the 14 non-mucinous LADCs with IHC performed, 5 (36%) were TTF-1-negative and all displayed poorly differentiated morphology. Overall, 8/10 (80%) of poorly differentiated components in non-mucinous LADCs were negative for TTF-1. In contrast, all LADCs with better differentiated patterns (acini/papillary/lepidic) were positive for TTF-1. The majority (14/21, 67%) of patients with available follow-up presented with metastasis. Full article

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11 pages, 1812 KB

Open AccessArticle

Association of SLC7A5/LAT1 Expression with Clinicopathological Parameters and Molecular Subtypes: Could It Be Considered in the Management of Breast Cancer?

by Nausheen Henna, Bellary Kuruba Manjunatha Goud, Rajani Dube, Sarah Riaz, Akhtar Sohail Chughtai and Abdul Hannan Nagi

J. Mol. Pathol. 2025, 6(4), 27; https://doi.org/10.3390/jmp6040027 - 14 Nov 2025

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Abstract

Introduction: Breast cancer is a heterogeneous malignancy influenced by diverse molecular profiles. The L-type amino acid transporter 1 (LAT1), encoded by the SLC7A5 gene, plays a key role in tumor metabolism, growth, and angiogenesis. Through its role in amino acid transport and activation [...] Read more.

Introduction: Breast cancer is a heterogeneous malignancy influenced by diverse molecular profiles. The L-type amino acid transporter 1 (LAT1), encoded by the SLC7A5 gene, plays a key role in tumor metabolism, growth, and angiogenesis. Through its role in amino acid transport and activation of the mTORC1 signaling pathway, LAT1 has emerged as a potential therapeutic target. Objective: To evaluate SLC7A5/LAT1 expression and its association with clinicopathological parameters and molecular subtypes of invasive carcinoma of no special type (NST) in a Pakistani cohort. Methods: Eighty-three patients who underwent mastectomy or modified radical mastectomy for histologically confirmed primary invasive carcinoma of no special type were included. Immunohistochemistry was used to assess SLC7A5/LAT1 expression. Associations with clinicopathological features and molecular groups were analyzed using the Chi-square test. Results: The mean age of SLC7A5-positive patients were 48.4 ± 10.8 years. Overall, 24.1% of patients demonstrated SLC7A5 positivity. Although SLC7A5 expression was more frequent in cases categorized as having moderate or poor prognosis based on the Nottingham Prognostic Index (NPI), this trend was not statistically significant. Similarly, no significant associations were observed between SLC7A5 expression and other clinicopathological or molecular variables. Conclusions:SLC7A5/LAT1 expression was identified in approximately one-quarter of invasive breast carcinoma cases. Its expression appeared more common in tumors with poorer NPI categories, but without statistically verified associations. These findings suggest that SLC7A5 may act independently of conventional clinicopathological parameters. Larger, longitudinal studies with survival follow-up are required to clarify its prognostic and therapeutic significance. Full article

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15 pages, 1965 KB

Open AccessArticle

Influence of Diabetes on Expression of Ezrin and MMP-2 in Gingival Tissue of Patients with Periodontal Disease

by Ionut Catalin Botezatu, Maria Luiza Baean, Maria-Alexandra Martu, Ana Emanuela Botez, Cristina Daniela Dimitriu, Carmen Solcan, Anca Ileana Sin, Claudiu Topoliceanu, Elena-Carmen Cotrutz and Oana Elena Ciurcanu

J. Mol. Pathol. 2025, 6(4), 26; https://doi.org/10.3390/jmp6040026 - 31 Oct 2025

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Abstract

Background: The aim of this study was to determine Ezrin and MMP-2 immunohistochemical expressions in the gingival tissue of patients with or without diabetes and to determine the role of the molecular pattern involvement in the evolution of periodontal disease. Material and Methods: [...] Read more.

Background: The aim of this study was to determine Ezrin and MMP-2 immunohistochemical expressions in the gingival tissue of patients with or without diabetes and to determine the role of the molecular pattern involvement in the evolution of periodontal disease. Material and Methods: In this histological study, we investigated 53 subjects with periodontal disease (test group—27 patients with type 2 DM; control—26 patients without diabetes). Samples from both groups were subjected to the immunohistochemistry (IHC) technique to evaluate the immunoreactivity (IR) intensity of Ezrin and MMP-2. Results: Among diabetic patients with periodontitis, 55.4% of patients exhibited intensely positive expression (+++) of Ezrin, and 44.6% of patients showed moderate expression (++) of Ezrin. All patients with diabetes and periodontitis showed intensely positive expression for MMP-2. In contrast, the control group showed negative expressions of Ezrin and MMP-2 (-) in 100% of cases. Significant statistical differences were found between Ezrin and MMP-2 expression in gingival samples of diabetic patients and non-diabetic patients with periodontal disease (p < 0.05). Conclusions: Ezrin and MMP-2 are significantly overexpressed in patients with diabetes and stage 2–3 periodontitis compared with non-diabetic patients with periodontal disease. Ezrin showed an exclusive pattern of moderate to strong positive staining in the diabetes–periodontitis group and complete absence in controls. MMP-2 displayed a broader range of staining intensities, with a predominance of strong positivity in all locations. Ezrin may represent a more consistent discriminative marker, whereas MMP-2 reflects a wider spectrum of tissue activation related to inflammation and tissue remodeling. Full article

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15 pages, 1128 KB

Open AccessReview

Hypoxia-Inducible Factor Prolyl Hydroxylase (HIF-PHD) Inhibitors: A Therapeutic Double-Edged Sword in Immunity and Inflammation

by Qinyun Li and Nik Nasihah Nik Ramli

J. Mol. Pathol. 2025, 6(4), 25; https://doi.org/10.3390/jmp6040025 - 28 Oct 2025

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Abstract

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors, clinically established for treating renal anemia, are emerging as potent immunomodulators with therapeutic potential far beyond erythropoiesis. This review dissects the mechanistic basis of their action, centered on the stabilization of hypoxia-inducible factor-alpha (HIF-α), a master transcription [...] Read more.

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitors, clinically established for treating renal anemia, are emerging as potent immunomodulators with therapeutic potential far beyond erythropoiesis. This review dissects the mechanistic basis of their action, centered on the stabilization of hypoxia-inducible factor-alpha (HIF-α), a master transcription factor that orchestrates fundamental shifts in immune cell function. We synthesize evidence showing how HIF-α stabilization alters innate immunity, recalibrates T- and B-cell responses, and reshapes inflammatory signaling. This activity translates to significant efficacy in preclinical models of autoimmune disorders, organ fibrosis, and ischemia–reperfusion injury. However, their broader clinical translation is hindered by a critical paradox in oncology. While HIF-α can potentiate anti-tumor immunity, its sustained activation risks promoting malignancy by driving angiogenesis, metabolic reprogramming, and fostering an immunosuppressive tumor microenvironment. Addressing this duality, alongside the potential for long-term immune dysregulation, is paramount. Future development must therefore prioritize precision-targeting strategies to harness the therapeutic benefits of HIF-PHD inhibitors while mitigating their pro-tumorigenic liabilities. Full article

(This article belongs to the Special Issue Pathology and Molecular Biology of Inflammatory Diseases)

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J. Mol. Pathol., Volume 6, Issue 4 (December 2025) – 9 articles

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