<h2>Summary</h2> In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2−/MMP7−) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

Simple Summary Both invasive placentation and cancer metastasis involve the intricate migration and invasion of cells into the surrounding tissues, while also creating new blood vessels to support their growth. The complex interplay of molecular signals that regulate cell behavior, including growth factors, cytokines, and extracellular matrix components, plays a crucial role in both processes. Despite their differing physiological contexts and evolutionary origins, invasive placentation and cancer metastasis share many molecular and cellular mechanisms that allow them to invade and proliferate in the surrounding tissues. In both pathological conditions, cells need to overcome the local mechanisms of immunological defense, activate invasion, and induce angiogenesis. This article focuses on describing the biomolecules that link these pathological processes. Abstract The process of epithelial-to-mesenchymal transition (EMT) is crucial in the implantation of the blastocyst and subsequent placental development. The trophoblast, consisting of villous and extravillous zones, plays different roles in these processes. Pathological states, such as placenta accreta spectrum (PAS), can arise due to dysfunction of the trophoblast or defective decidualization, leading to maternal and fetal morbidity and mortality. Studies have drawn parallels between placentation and carcinogenesis, with both processes involving EMT and the establishment of a microenvironment that facilitates invasion and infiltration. This article presents a review of molecular biomarkers involved in both the microenvironment of tumors and placental cells, including placental growth factor (PlGF), vascular endothelial growth factor (VEGF), E-cadherin (CDH1), laminin γ2 (LAMC2), the zinc finger E-box-binding homeobox (ZEB) proteins, αVβ3 integrin, transforming growth factor β (TGF-β), β-catenin, cofilin-1 (CFL-1), and interleukin-35 (IL-35). Understanding the similarities and differences in these processes may provide insights into the development of therapeutic options for both PAS and metastatic cancer.

/pdf/biomolecules-involved-in-both-metastasis-and-placenta-hgxplb50.pdf

Biomolecules Involved in Both Metastasis and Placenta Accreta Spectrum—Does the Common Pathophysiological Pathway Exist?

Abstract Objectives Gastric cancer (GC) is a prevalent malignant tumor widely distributed globally, exhibiting elevated incidence and fatality rates. The gene LAMC2 encodes the laminin subunit gamma-2 chain and is found specifically in the basement membrane of epithelial cells. Its expression is aberrant in multiple types of malignant tumors. This research elucidated a link between LAMC2 and the clinical characteristics of GC and investigated the potential involvement of LAMC2 in GC proliferation and advancement. Materials and methods LAMC2 expressions were detected in GC cell lines and normal gastric epithelial cell lines via qRT-PCR. Silencing and overexpression of the LAMC2 were conducted by lentiviral transfection. A xenograft mouse model was also developed for in vivo analysis. Cell functional assays were conducted to elucidate the involvement of LAMC2 in cell growth, migration, and penetration. Further, immunoblotting was conducted to investigate the impact of LAMC2 on the activation of signal pathways after lentiviral transfection. Results In the findings, LAMC2 expression was markedly upregulated in GC cell lines as opposed to normal gastric epithelial cells. In vitro analysis showed that sh - LAMC2 substantially inhibited GC cell growth, migration, and invasion, while oe - LAMC2 displayed a contrasting effect. Xenograft tumor models demonstrated that oe-LAMC2 accelerated tumor growth via high expression of Ki-67. Immunoblotting analysis revealed a substantial decrease in various signaling pathway proteins, PI3K, p-Akt, and Vimentin levels upon LAMC2 knockdown, followed by increased E-cadherin expression. Conversely, its overexpression exhibited contrasting effects. Besides, epithelial-mesenchymal transition (EMT) was accelerated by LAMC2. Conclusion This study provides evidence indicating that LAMC2, by stimulating signaling pathways, facilitated EMT and stimulated the progression of GC cells in laboratory settings and mouse models. Research also explored that the abnormal LAMC2 expression acts as a biomarker for GC. 

LAMC2 regulates the proliferation, invasion, and metastasis of gastric cancer via PI3K/Akt signaling pathway

Abstract Background Airway remodelling plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Epithelial–mesenchymal transition (EMT) is a significant process during the occurrence of airway remodelling. Increasing evidence suggests that glucose transporter 3 (GLUT3) is involved in the epithelial mesenchymal transition (EMT) process of various diseases. However, the role of GLUT3 in EMT in the airway epithelial cells of COPD patients remains unclear. Methods We detected the levels of GLUT3 in the peripheral lung tissue of COPD patients and cigarette smoke (CS)-exposed mice. Two Gene Expression Omnibus GEO datasets were utilised to analyse GLUT3 gene expression profiles in COPD. Western blot and immunofluorescence were used to detect GLUT3 expression. In addition, we used the AAV9-GLUT3 inhibitor to reduce GLUT3 expression in the mice model. Masson’s staining and lung function measurement were used detect the collagen deposition and penh in the mice. A cell study was performed to confirm the regulatory effect of GLUT3. Inhibition of GLUT3 expression with siRNA, Western blot, and immunofluorescence were used to detect the expression of E-cadherin, N-cadherin, vimentin, p65, and ZEB1. Results Based on the GEO data set analysis, GLUT3 expression in COPD patients was higher than in non-smokers. Moreover, GLUT3 was highly expressed in COPD patients, CS exposed mice, and BEAS-2B cells treated with CS extract (CSE). Further research revealed that down-regulation of GLUT3 significantly alleviated airway remodelling in vivo and in vitro. Lung function measurement showed that GLUT3 reduction reduced airway resistance in experimental COPD mice. Mechanistically, our study showed that reduction of GLUT3 inhibited CSE-induced EMT by down-regulating the NF-κB/ZEB1 pathway. Conclusion We demonstrate that CS enhances the expression of GLUT3 in COPD and further confirm that GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway; these findings have potential value in the diagnosis and treatment of COPD. The down-regulation of GLUT3 significantly alleviated airway remodelling and reduced airway resistance in vivo. Our observations uncover a key role of GLUT3 in modulating airway remodelling and shed light on the development of GLUT3-targeted therapeutics for COPD. 

GLUT3-mediated cigarette smoke-induced epithelial-mesenchymal transition in chronic obstructive pulmonary disease through the NF-kB/ZEB1 pathway

With the emergence of targeted inhibition strategies for Hedgehog signaling in cancer, multiple Hedgehog signaling pathway-related biomarkers have become the focus of research. SsGSEA algorithm was employed to analyze the Hedgehog pathway scores of samples in TCGA-HNSC dataset and divide them into two groups. Weighted co-expression network analysis was performed to identify modules strongly associated with the Hedgehog pathway. Differentially up-regulated genes in tumor samples in comparison to the normal ones were screened by Limma, in which genes belonging to modules strongly related to Hedgehog pathway were further filtered by LASSO reduction and multivariate Cox regression analysis to develop a model. ESTIMATE and CIBERSORT were served to characterize the tumor microenvironment (TME). TIDE assessed immunotherapy response. Hedgehog pathway activity was significantly higher in head and neck squamous cell carcinoma (HNSCC) tissues than in normal tissues and was correlated with HNSCC survival, glycan, cofactors and vitamins, drug metabolism, and matrix scores. Six genes (SLC2A3, EFNB2, OAF, COX4I2, MT2A and TXNRD1) were captured to form a Hedgehog associated 6-gene signature, and the resulting risk score was an independent indicator of HNSCC prognosis. It was significantly positively correlated with stromal score, metabolism, angiogenesis and inflammatory response. Patients in low-risk group with a low TIDE score had higher immunotherapy sensitivity relative to those in high-risk group. This study revealed novel findings of the Hedgehog pathway in HNSCC progression and opened up a Hedgehog pathology-related signature to help identify risk factors contributing to HNSCC progression and help predict immunotherapy outcomes. 

pdf/elucidating-hedgehog-pathway-s-role-in-hnscc-progression-huqdofyzve.pdf

Elucidating Hedgehog pathway's role in HNSCC progression: insights from a 6-gene signature

Objectives Accumulating evidence suggested that the laminin γ2 (LAMC2) expression level was upregulated in various cancers. However, the potential prognostic value of LAMC2 in cancers remains unclear. We conducted a meta-analysis to clarify the association of LAMC2 expression with prognosis. Design We searched Embase, Web of Science and PubMed (up to 25 November 2021) to collect all eligible studies, and meta-analysis was performed to interpret the association of LAMC2 expression with clinicopathological parameters, overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS). Eligibility criteria for including studies We included studies that investigate the relationship between LAMC2 and prognosis of cancers, patients were divided into two groups, and associations of LAMC2 expression with clinicopathological features were described. Results Seven studies were finally included. We found that increased LAMC2 expression was significantly associated with lymph node metastasis (log OR 0.88, 95% CI 0.38 to 1.38, p<0.001), tumour-node-metastasis stages (log OR: 0.95, 95% CI 0.39 to 1.50, p<0.001) and tumour status (log OR 1.26, 95% CI 0.84 to 1.68, p<0.001), but not with age (log OR −0.05, 95% CI −0.37 to 0.27, p=0.75) or gender (log OR −0.07, 95% CI −0.52 to 0.38, p=0.75). In addition, higher LAMC2 expression was found to be significantly associated with OS/PFS/DSS (HR 1.85, 95% CI 1.31 to 2.40, p<0.001). A similar result was found in The Cancer Genome Atlas database. High LAMC2 expression was significantly associated with OS in lung adenocarcinoma, mesothelioma, skin cutaneous melanoma, neck squamous cell carcinoma and brain lower grade glioma. Conclusion Our results suggested that higher LAMC2 expression was correlated with worse survival, lymph node metastasis, tumour-node-metastasis stages and tumour status. This study was subject to inherent limitations, but the results presented here provide insights regarding the potential use of LAMC2 as a biomarker for human cancer. Study registration researchregistry.com (researchregistry1319).

/pdf/lamc2-as-a-prognostic-biomarker-in-human-cancer-a-systematic-39cmobn1.pdf

LAMC2 as a prognostic biomarker in human cancer: a systematic review and meta-analysis

ABSTRACT SLC2A3 is an important member of the glucose transporter superfamily. It has been recently suggested that upregulation of SLC2A3 is associated with poor survival and acts as a prognostic marker in a variety of tumors. Unfortunately, the prognostic role of SLC2A3 in head and neck squamous cell carcinoma (HNSC) is less known. In the present study, we analyzed SLC2A3 expression in HNSC and its correlation with prognosis using TCGA and GEO databases. The results showed that SLC2A3 mRNA expression was higher in HNSC compared with adjacent normal tissues, which was validated with our 9 pairs of HNSC specimens. Moreover, high SLC2A3 expression predicted poor prognosis in HNSC patients. Mechanistically, GSEA revealed that high expression of SLC2A3 was enriched in epithelial-mesenchymal transition (EMT) and NF-κB signaling. In HNSC cell lines, SLC2A3 knockdown inhibited cell proliferation and migration. In addition, NF-κB P65 and EMT-related gene expression was suppressed upon SLC2A3 knockdown, indicating that SLC2A3 may play a preeminent role in the progression of HNSC through the NF-κB/EMT axis. Meanwhile, the expression of SLC2A3 was negatively correlated with immune cells, suggesting that SLC2A3 may be involved in the immune response in HNSC. The correlation between SLC2A3 expression and drug sensitivity was further assessed. In conclusion, our study demonstrated that SLC2A3 could predict the prognosis of HNSC patients and mediate the progression of HNSC via the NF-κB/EMT axis and immune responses.

https://www.tandfonline.com/doi/pdf/10.1080/19336950.2023.2208928?needAccess=true&role=button

Identification of SLC2A3 as a prognostic indicator correlated with the NF-κB/EMT axis and immune response in head and neck squamous cell carcinoma

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LAMC2 as a prognostic biomarker in human cancer: a systematic review and meta-analysis

Identification of SLC2A3 as a prognostic indicator correlated with the NF-κB/EMT axis and immune response in head and neck squamous cell carcinoma