Tumor Lymphatic Metastasis Research Articles

LncRNAs in serum-derived extracellular vesicles are potential biomarker and correlated with immune infiltration in gastric cancer

BackgroundLong non-coding RNAs (lncRNAs) in extracellular vesicles (EVs) have been confirmed as effective non-invasive biomarkers for multiple diseases. However, their expression and clinical value in gastric cancer (GC) remain poorly understood.Materials and methodsSerum EV RNA was extracted from four patients with GC and four healthy controls, followed by high-throughput RNA sequencing. LncRNAs were further validated in training and validation sets using quantitative real-time reverse transcription polymerase chain reaction.ResultsA total of 37,684 lncRNAs were obtained, and 10 lncRNAs were selected based on the criteria (P < 0.05 and |log2FoldChange| ≥1). Serum EV lncRNA RMRP, RPPH1, and linc-ROR were significantly higher in patients with GC than in those with chronic gastritis, atypical hyperplasia, or healthy control (all P < 0.05). Three lncRNAs were also significantly correlated with tumor diameter, lymphatic metastasis, distal metastasis, and TNM stage (all P < 0.05). The area under the curve (AUC) values for lncRNA RMRP, RPPH1, and linc-ROR were 0.727, 0.774, and 0.811, respectively. Corresponding sensitivity and specificity were 63.4% and 85.4%, 50.7% and 89.6%, and 78.5% and 66.7%. The combination of these three lncRNAs with carcinoembryonic antigen (CEA) yielded an AUC of 0.909, with a sensitivity and specificity of 83.3% each. Furthermore, high EV linc-ROR and RMRP expression levels were associated with worse disease-free survival and overall survival (OS). Univariate and multivariate Cox regression analyses confirmed that linc-ROR was the only independent prognostic factor for GC. Finally, the lncRNA-miRNA-mRNA network showed that three lncRNAs were predicted to interact with 15 miRNAs and 69 mRNAs. In addition, lncRNA RMRP and linc-ROR were correlated with immune cell infiltration, including neutrophils, central memory CD4 T cells, macrophage, and natural kill T cells.ConclusionEV lncRNAs are prospective biomarker and correlated with immune cell infiltration in GC. It provides a foundation for the development of serum EV-targeted novel biomarkers and immunotherapy targets of GC.

Pan-Cancer Analysis of the Prognostic and Immunotherapeutic Value of PDGFB.

Cancer is a widespread epidemic that affects millions of individuals across the world. Identifying novel cancer targets is crucial to developing more effective cancer treatments. Platelet-derived growth factor-B (PDGFB) plays a critical role in various tumor processes, including angiogenesis and lymphatic metastasis. However, there is a lack of research on the role of PDGFB in these processes. To address this issue, we conducted a comprehensive analysis utilizing multiple online databases to investigate the expression, prognostic, tumor stemness, and immunological effect of PDGFB. In addition, clinical samples were validated using immunohistochemistry. Our findings revealed that PDGFB was highly expressed in a diverse range of cancer types, and its expression and genetic modifications were significantly associated with clinical outcomes in certain tumors. In general, high expression of PDGFB in tumors is associated with poor prognosis. Surprisingly, PDGFB was found to be highly expressed in renal clear cell carcinoma but was associated with good prognosis. In contrast, PDGFB was low expressed in lung carcinoma, but its expression was found to improve patient survival. These findings demonstrate the complex role of PDGFB in different cancer types. The study also demonstrated that PDGFB was linked to RNA and DNA stemness in 15 and 36 tumor types, respectively, and had a positive association with tumor lymphocyte infiltration. Notably, PDGFB was found to be associated with immune modulators. PDGFB, which is involved in various immune responses, influences the malignant characteristics of various cancer types and controls immune cell infiltration. We confirmed that PDGFB positively correlated with CD8 and PDL1 expression in lower grade glioma. This study concludes that PDGFB may serve as a potential prognostic marker and a potential targetable pathway in cancer immunotherapy. Overall, the study sheds new light on the role of PDGFB in cancer and highlights its potential clinical significance.

Regulatory T cells crosstalk with tumor cells and endothelium through lymphotoxin signaling

Regulatory T cells (Tregs) with multifaceted functions suppress anti-tumor immunity by signaling surrounding cells. Here we report Tregs use the surface lymphotoxin (LT)α1β2 to preferentially stimulate LT beta receptor (LTβR) nonclassical NFκB signaling on both tumor cells and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LTβR nonclassical NFκB pathway inhibits tumor growth and migration in vitro. Leveraging in vivo Treg LTα1β2 interactions with LTβR on tumor cells and LECs, transfer of wild type but not LTα-/- Tregs promotes B16F10 melanoma growth and tumor cell-derived chemokines in LTβR-/- mice; and increases SOX18 and FLRT2 in lymphatic vessels of LTβR-/- melanoma. Blocking the nonclassical pathway suppresses tumor growth and lymphatic metastasis by reducing chemokine production, restricting Treg recruitment to tumors, and retaining intratumoral IFNγ+ CD8 T cells. Our data reveals that Treg LTα1β2 promotes LTβR nonclassical NFκB signaling in tumor cells and LECs providing a rational strategy to prevent Treg promoted tumor growth and metastasis.

Detection of genetic mutations in 855 cases of papillary thyroid carcinoma by next generation sequencing and its clinicopathological features

ObjectiveTo investigate the genetic mutations in patients with papillary thyroid carcinoma (PTC) and their clinicopathological features by next generation sequencing (NGS).MethodsNGS technology was used to detect genetic mutations in PTC patients, and clinicopathological features were collected.Results①Among 855 PTC patients, 810 patients had genetic mutations, and 45 patients had no genetic mutation. ②BRAF mutation was associated with tumor diameter (P < 0.001) and histological subtypes (P = 0.002). The abundance of V600E mutation was associated with gender (P = 0.004), tumor diameter (P < 0.001), bilateral presentation (P = 0.001), extrathyroidal extension (P < 0.001), lymphatic metastasis (P < 0.001), histological subtypes (P = 0.002) and TNM staging (P = 0.000); The different mutation abundance of V600E was associated with tumor diameter (P < 0.001), multifocal presentation (P = 0.047), bilateral presentation (P = 0.001), extrathyroidal extension (P = 0.001), lymphatic metastasis (P < 0.001), histological subtypes (P = 0.022) and TNM staging (P = 0.000). ③RET fusion was associated with tumor diameter (P < 0.001) and lymphatic metastasis (P = 0.005). ④TERT mutation was associated with gender (P = 0.043), tumor diameter (P < 0.001), extrathyroidal extension (P = 0.028) and TNM staging (P = 0.017). ⑤RAS mutation was associated with histological subtypes (P < 0.001). ⑥NTRK and PIK3CA mutations were not associated with clinicopathological features.ConclusionNGS technology can comprehensively analyze the genetic mutations in PTC patients, which provides important prompts for the occurrence, development, diagnosis and treatment of PTC. In addition, BRAF V600E mutation, RET fusion and TERT mutation are associated with a number of high-risk clinicopathological features. Detection of genetic mutations in PTC patients by NGS is of great significance.

Whole-exome sequencing reveals novel genomic signatures and potential therapeutic targets during the progression of rectal neuroendocrine neoplasm

Rectal neuroendocrine neoplasms (rNENs) are among the most frequent gastrointestinal neuroendocrine neoplasms and pose a serious challenge for clinical management. The size of the primary neoplasm is considered to be the most important predictor of disease progression, but the genetic alterations that occur during the progression of rNENs remain unknown. Here, we performed a comprehensive whole-exome sequencing study on 54 tumor-normal paired, formalin-fixed paraffin-embedded specimens from patients locally diagnosed with rNENs. Of these, 81.5% (n = 44) were classified as small-sized (≤2 cm) rNENs, while the remainder (18.5%, n = 10) were classified as large-sized (>2 cm) rNEN samples. Comparative analysis revealed marked disparities in the mutational landscape between small- and large-sized rNEN samples, and between large-sized rNEN samples with or without lymph node metastases. The high-confidence driver genes RHPN2, MUC16, and MUC4 were significantly mutated in both small- and large-sized rNEN specimens, whereas mutations in MAN2A1, and BAG2 were only identified in large-sized specimens diagnosed with lymph node metastases. Correspondingly, we observed that the mTOR and MAPK pathways were preferentially enriched in the large-sized rNEN specimens. Signature-based analysis revealed that mutational processes associated with defective DNA base excision repair (SBS30) significantly accumulated in large-sized rNEN samples with lymph node metastases, highlighting the important role of this mutagenic process in promoting rNEN progression. We further found that most rNEN subjects, regardless of tumor size, harbored at least one alteration with targeted therapeutic implications. Taken together, these results elucidate the genetic features associated with tumor size and lymphatic metastasis in rNEN patients, which will deepen our understanding of the genetic changes during rNEN progression and potentially directing improvements in rNEN treatment strategies.

LEF1 is associated with immunosuppressive microenvironment of patients with lung adenocarcinoma.

Wnt/β-Catenin pathway plays an important role in the occurrence and progression of malignant tumors, especially PD-L1-mediated tumor immune evasion. However, the role of TCF/LEF, an important member of the Wnt/β-catenin pathway, in the tumor immunosuppressive microenvironment of lung adenocarcinoma (LUAD) remains unknown. LUAD tissue-coding RNA expression data from The Cancer Genome Atlas and TIMER databases were used to analyze the expression of TCF/LEF transcription factors and their correlation with various immune cell infiltration. Immunohistochemistry and immunofluorescence were used to detect tissue protein staining in 105 patients with LUAD. LEF1, TCF7, TCF7L1 and TCF7L2 were all aberrantly expressed in the tumor tissues of LUAD patients with the data from The Cancer Genome Atlas (TCGA) database, tumor immune estimation resource (TIMER) database and results of immunohistochemistry, but only LEF1 expression was associated with 5-year overall survival in LUAD patients. LEF1 protein expression was associated with advanced tumor node metastasis (TNM) stage, lymphatic metastasis and local invasion in 105 cases LUAD patients. At the same time, LEF1 mRNA expression was also associated with immunosuppressive microenvironment in LUAD patients with the data from TCGA database and TIMER database. Results of immunohistochemistry and immunofluorescence in tumor tissues of 105 cases LUAD patients showed that there was a positively correlation between LEF1 protein expression and the infiltration of M2 macrophages and Treg cells. LEF1 was highly expressed in tumor tissues of LUAD patients, and highly expressed LEF1 was associated with the immunosuppressive microenvironment of LUAD patients.

FBXO2 promotes the progression of papillary thyroid carcinoma through the p53 pathway

Emerging evidence have demonstrated that F-box only protein 2 (FBXO2) is intimately associated with malignant tumor development and occurrence. However, neither the functions nor the molecular mechanisms underlying FBXO2 have been determined in the papillary thyroid carcinoma (PTC). The quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were carried out to detect the FBXO2 expression in PTC tissues. CCK-8 assay, EdU assay and flow cytometry were used to assess cell proliferation, cell cycle and apoptosis. The trans-well assay was conducted to determine the cell invasiveness. The effect of FBXO2 on PTC cell proliferation in vivo was observed through a subcutaneous tumor formation experiment in nude mice. Immunoprecipitation were conducted to detect the interaction between FBXO2 and p53. The ubiquitination assays were conducted to assess the regulation of p53 ubiquitination by FBXO2. FBXO2 was overexpressed in both PTC tissues and cell lines. FBXO2 expression positively correlated with PTC tumor size, lymphatic metastasis, and extramembranous invasion. Furthermore, silencing FBXO2 inhibited PTC cell proliferation and promoted apoptosis. The overexpression of FBXO2 significantly promotes PTC cell proliferation. Mechanistic studies revealed that FBXO2 could directly bind to p53 and promote its ubiquitination degradation. Knockdown of p53 partially reversed the progression arrest induced by FBXO2 Knockdown in PTC cells. FBXO2 knockdown inhibited PTC cell proliferation and promoted apoptosis by targeting p53 for ubiquitination and degradation. This process represents a research foundation for its diagnostic and therapeutic applications.

Osteoblasts are induced into cancer-associated osteoblasts to promote tumor progression in head and neck squamous cell carcinoma

Bone invasion by head and neck squamous cell carcinoma (HNSCC) significantly impacts tumor staging, treatment choice, prognosis, and quality of life. While HNSCC is known to cause osteolytic bone invasion, we found that specific HNSCC subtypes can induce osteogenic bone destruction at the tumor-bone interface. This destruction mode significantly correlated with reduced patient survival rates and increased neck lymph node metastasis. Further in vivo and in vitro experiments indicated that HNSCC cells triggered abnormal phenotypic changes in osteoblasts to remodel the tumor-bone microenvironment, facilitating tumor lymphatic metastasis. Through transcriptome analysis, we identified three genes—osteopontin (SPP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and matrix metalloprotein (MMP)9 (MMP9) linked to a poorer prognosis. We discovered osteoblasts with abnormal phenotypes at the tumor-bone interface exhibiting high SPP1, MMP9, and CXCL1 expressions. Based on these characteristics, we identified this osteoblast subpopulation as “cancer-associated osteoblasts (CAOs).” HNSCC cells activated the TNF-α/NF-κB signaling pathway in osteoblasts, transforming them into “CAOs.” These CAOs significantly contributed to the progression of tumor-induced bone invasion, facilitating cancer growth and metastasis. We first provided clinical data and in vivo and in vitro evidence that HNSCC cells can promote tumor progression by manipulating osteoblasts into “CAOs” in the bone invasion.

Multifunctional Nanoprobe Au@Gd-SiO2-HA-Lyp-1/DOX with Dual-Targeting Functions Derived from HA and LyP-1: Diagnostic and Therapeutic Potential for Tumor Lymphatic Metastasis.

To address lymphatic metastasis in lung cancer, we developed the Au@Gd-SiO2-HA-LyP-1 nanoprobe, assessing its diagnostic and therapeutic capabilities. This nanoprobe integrates a Au core with a Gd-SiO2 shell and dual-targeting HA-LyP-1 molecules. We evaluated its size, shape, and functional properties using various characterization techniques, alongside in vivo and in vitro toxicity tests. The spherical nanoprobes have a 50 nm diameter and contain 1.37% Gd. They specifically target lymphatic metastasis sites and tumor cells, showing enhanced MRI contrast and effective, targeted DOX delivery with reduced normal tissue toxicity. The Au@Gd-SiO2-HA-LyP-1 nanoprobe is a promising tool for diagnosing and treating lung cancer lymphatic metastasis, featuring dual-targeting and superior imaging capabilities.

Long non-coding RNA LINC00930 targeting miR-6792-3p/ZBTB16 regulates the proliferation and EMT of pancreatic cancer

Emerging evidence suggests the dysregulation of long non-coding RNAs (lncRNAs) involved in pancreatic cancer (PC). However, the function of LINC00930 in PC has not been elaborated. In this study, we found that LINC00930 was significantly down-regulated in PC cell lines and tissues, and associated with tumor size, lymphatic metastasis, TNM stage and poor prognosis. According to the bioinformatics database, the downregulation of LINC00930 was a common event in PC associated with prognosis and EMT. Overexpression of LINC00930 inhibited the aggressive cancer phenotypes including proliferation, metastasis and epithelial-mesenchymal transition (EMT) of PC in vitro and in vivo. Bioinformatics and dual-luciferase reporter assay indicated that miR-6792-3p could directly bind to LINC00930. Additionally, the Zinc finger and BTB domain containing 16 (ZBTB16) was significantly declined in PC, which was predicted to be the downstream gene of miR-6792-3p. MiR-6792-3p mimic rescued the decreased proliferation, metastasis and EMT caused by ZBTB16 in PC cells. The LINC00930/miR-6792-3p/ZBTB16 axis was associated with the malignant progression and process of PC. The relative expression of LINC00930 was negatively correlated with the expression of miR-6792-3p and was closely linked with ZBTB16 levels in PC. LINC00930 might serve as a potential prognostic biomarker and therapeutic target for PC.

Matricellular proteins: Potential biomarkers in head and neck cancer.

The extracellular matrix (ECM) is a complex network of diverse multidomain macromolecules, including collagen, proteoglycans, and fibronectin, that significantly contribute to the mechanical properties of tissues. Matricellular proteins (MCPs), as a family of non-structural proteins, play a crucial role in regulating various ECM functions. They exert their biological effects by interacting with matrix proteins, cell surface receptors, cytokines, and proteases. These interactions govern essential cellular processes such as differentiation, proliferation, adhesion, migration as well as multiple signal transduction pathways. Consequently, MCPs are pivotal in maintaining tissue homeostasis while orchestrating intricate molecular mechanisms within the ECM framework. The expression level of MCPs in adult steady-state tissues is significantly low; however, under pathological conditions such as inflammation and cancer, there is a substantial increase in their expression. In recent years, an increasing number of studies have focused on elucidating the role and significance of MCPs in the development and progression of head and neck cancer (HNC). During HNC progression, there is a remarkable upregulation in MCP expression. Through their distinctive structure and function, they actively promote tumor growth, invasion, epithelial-mesenchymal transition, and lymphatic metastasis of HNC cells. Moreover, by binding to integrins and modulating various signaling pathways, they effectively execute their biological functions. Furthermore, MCPs also hold potential as prognostic indicators. Although the star proteins of various MCPs have been extensively investigated, there remains a plethora of MCP family members that necessitate further scrutiny. This article comprehensively examines the functionalities of each MCP and highlights the research advancements in the context of HNC, with an aim to identify novel biomarkers for HNC and propose promising avenues for future investigations.

Clinical significance of miR-9-5p in NSCLC and its relationship with smoking.

Dysregulated expression of microRNA (miRNAs) in lung cancer has been wildly reported. The clinicopathologic significance of miR-9-5p in non-small-cell lung cancer (NSCLC) patients and its effect on NSCLC progression were explored in this study. A total of 76 NSCLC patients were included. miR-9-5p expression was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, in vitro experiments including cell growth curve assays, colony formation assays, and transwell migration assays were performed. Further clinicopathological and prognostic values were explored using bioinformatics analysis of the TCGA database. miR-9-5p expression was significantly increased in tumor tissues (both P < 0.0001). miR-9-5p expression was relatively higher in larger tumors (P = 0.0327) and in lung squamous carcinoma (LUSC) (P = 0. 0143). In addition, miR-9-5p was significantly upregulated in the normal lung tissues of cigarette smokers (P = 0.0099). In vitro, miR-9-5p was correlated with cell proliferation and migration. After that, bioinformatics analysis of the TCGA database indicated that miR-9-5p was correlated with tumor size (P = 0.0022), lymphatic metastasis (P = 0.0141), LUSC (P < 0.0001), and smoking history (P < 0.0001). Finally, a prognostic study indicated high miR-9-5p expression was correlated with poor prognosis in LUAD (P = 0.0121). Upregulation of miR-9-5p may have an oncogenic effect in NSCLC and may be related to smoking. The conclusion of this study may help find new prognostic and therapeutic targets for NSCLC and the exploration of the relationship between smoking and lung cancer.

The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma

BackgroundEpithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients.MethodsWe retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021.ResultsA total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated.ConclusionsThe combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma.Trial registrationThis study was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Clinical effect of neoadjuvant chemotherapy combined with laparoscopic surgery for patients with colorectal cancer

Purpose: To assess the clinical effect of neoadjuvant chemotherapy in combination with laparoscopic surgery in treating progressive colorectal cancer.&#x0D; Methods: 90 patients with colorectal cancer admitted to Hebei Yanda Hospital, Hebei Langfang, China between December 2020 and December 2021 were enrolled. The patients were randomly grouped into control and study groups. Control group underwent laparoscopic surgery while the study group underwent neoadjuvant chemotherapy in addition to laparoscopic surgery. Gastrointestinal function recovery time, tumor control effect, tumor marker level, and adverse reactions were investigated and compared between the two groups.&#x0D; Results: Time to anal exhaust, time to first defecation, time to first solid food intake, and time to recover to normal bowel sounds were earlier in the study group compared to control group (p &lt; 0.05). Study group exhibited a greater overall rate of tumor control response., while the rate of tumor lymphatic metastasis was also significant (p &lt; 0.05). After treatment, the study group exhibited significantly lower levels of tumor markers compared to control group (p &lt; 0.05). The occurrence of adverse reactions was not significant between the two groups (p &gt; 0.05).&#x0D; Conclusion: Neoadjuvant chemotherapy in conjunction with laparoscopic surgery in the treatment of progressive rectal cancer improves patient outcomes and enhances prognosis.

Synergistic Phototherapy-Molecular Targeted Therapy Combined with Tumor Exosome Nanoparticles for Oral Squamous Cell Carcinoma Treatment.

Oral squamous cell carcinoma (OSCC) contributes to more than 90% of all oral malignancies, yet the performance of traditional treatments is impeded by limited therapeutic effects and substantial side effects. In this work, we report a combinational treatment strategy based on tumor exosome-based nanoparticles co-formulating a photosensitizer (Indocyanine green) and a tyrosine kinase inhibitor (Gefitinib) (IG@EXOs) for boosting antitumor efficiency against OSCC through synergistic phototherapy-molecular targeted therapy. The IG@EXOs generate distinct photothermal/photodynamic effects through enhanced photothermal conversion efficiency and ROS generation, respectively. In vivo, the IG@EXOs efficiently accumulate in the tumor and penetrate deeply to the center of the tumor due to passive and homologous targeting. The phototherapy effects of IG@EXOs not only directly induce potent cancer cell damage but also promote the release and cytoplasmic translocation of Gefitinib for achieving significant inhibition of cell proliferation and tumor angiogenesis, eventually resulting in efficient tumor ablation and lymphatic metastasis inhibition through the synergistic phototherapy-molecular targeted therapy. We envision that the encouraging performances of IG@EXOs against cancer pave a new avenue for their future application in clinical OSCC treatment.

Angiopoietin-2 expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma.

The aim of this study was to investigate angiopoietin-2 (Ang-2/ANGPT2) expression and its relationship with lymphangiogenesis and clinicopathological characteristics in cutaneous malignant melanoma (CMM). Gene expression differences between metastatic melanoma and melanoma in situ in 472 patients from the TCGA database were analyzed. The target gene Ang-2 was screened. A clinical study was conducted to analyze the correlation between Ang-2 expression in CMM and tumor-associated lymphangiogenesis. A total of 42 patients with primary CMM who underwent extended tumor resection procedures at the Affiliated Hospital of Jiangsu University were included in this study. Clinical data (gender, age, lymph node metastasis, Breslow thickness, and clinical stage) were collected. The expression levels of both Ang-2 and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) proteins were detected by immunohistochemistry (IHC). Lymphatic vascular density (LVD) was counted by using LYVE-1 to label lymphatic endothelial cells (LECs) in peritumoral and intratumoral areas per high-magnification field of view. Statistical analysis was performed using the Pearson correlation test and Student's t-test. Using the TCGA database, it was found that the gene expression level of Ang-2 in 368 cases of metastatic melanoma was significantly higher than that in 104 cases of melanoma in situ. Correlation analysis showed a significant relationship between Ang-2 and LYVE-1, and vascular endothelial growth factor receptor 3(VEGFR3) expression, respectively, in CMM. Moreover, the optimal cutoff value of survival analysis showed that high Ang-2 expression in CMM had a worse prognosis, based on data from the TCGA database. Our research showed that Ang-2 was more highly expressed in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients than in the group of patients with no lymph node metastasis and in the group of stage 0-3B patients. Our research also showed that LVD in the group of patients with lymph node metastasis and in the group of stage 3C-4 patients was significantly higher than that in the group of no lymph node metastasis and in the group of stage 0-3B patients, respectively. Breslow thickness also correlated with Ang-2 expression and LVD. Ang-2 expression was not related to sex or age. Ang-2 expression was obviously correlated with LVD. An evaluation of Ang-2 expression and LVD can be used to predict the risk of tumor lymphatic metastasis and determine the prognosis of CMM. These results may also provide a new clinical treatment strategy for CMM.

Protein@cyanine-based NIR-II lymphography enables the supersensitive visualization of lymphedema and tumor lymphatic metastasis.

Visualization of the lymphatic system is clinically indispensable for the diagnosis and/or treatment of lymphatic diseases. Although indocyanine green (ICG) lymphography becomes an alternate imaging modality compared to traditional lymphoscintigraphy, it's still far from ideal due to the insufficient detection depth and low spatiotemporal resolution. Herein, w e rationally develop protein@cyanine probes to solve the limitations of the current NIR-I lymphography. The protein@cyanine probes are synthesized following a chlorine-containing dye-labeling strategy based on structure-selectivity (facile covalent binding between the dye and protein with a 1:1 molar ratio). As expected, ou r probes display exceptional NIR-II imaging ability with much-improved imaging contrast/resolution and controllable pharmacokinetics, superior to the clinical ICG. Ou r protein@cyanine probes locate lymph nodes (LNs) and delineate lymphatic vessels (LVs) with super-high sensitivity and signal-to-background ratio, enabling real-time diagnosing lymphatic diseases such as lymphedema and tumor lymphatic metastasis. In particular, the NIR-II lymphography provides us an opportunity to discover the disparate morbidity rate of primary lymphedema in different types of mice. Given the fact of lacking clinically transferable NIR-II probes, this work not only provides a promising strategy for enriching of the current library of NIR-II probes, but also promotes the clinical translation of NIR-II lymphography technology. This article is protected by copyright. All rights reserved.

The Role of PRMT7 and KLF4 in Driving the Malignant Progression of Gastric Cancer

This study investigates the impact of PRMT7 on the malignant behaviors of gastric cancer (GC) and explores its potential as a therapeutic target for GC treatment. Clinical specimens and cytological experiments were analyzed to assess the effects of PRMT7. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to measure relative levels of PRMT7 in 48 pairs of GC and adjacent normal tissues. The influence of PRMT7 on clinical features and prognosis in GC patients was examined. The regulatory effects of PRMT7 on proliferative and migratory potentials in GC cells were evaluated using cell counting kit-8 (CCK-8) and transwell assay, respectively. Additionally, the role of PRMT7 and its downstream target in regulating malignant behaviors of GC was elucidated. Results showed that PRMT7 was upregulated in GC tissues, and its high expression in GC patients was associated with tumor staging and lymphatic metastasis, indicating a poor prognosis. PRMT7 stimulated proliferative and migratory potentials in GC cells, and KLF4 was identified as the downstream gene of PRMT7 responsible for the PRMT7-mediated malignant phenotypes of GC. In conclusion, PRMT7 is upregulated in GC tissues and its elevated levels are closely linked to tumor staging and lymphatic metastasis, predicting an unfavorable prognosis. PRMT7 drives the proliferative and migratory potentials of GC cells through the negative regulation of KLF4. The findings suggest that PRMT7 could be a potential therapeutic target for GC.

Tumor Necrosis Factor-α Promotes the Tumorigenesis, Lymphangiogenesis, and Lymphatic Metastasis in Cervical Cancer via Activating VEGFC-Mediated AKT and ERK Pathways.

Lymphatic metastasis is a common phenomenon of cervical cancer. Tumor necrosis factor-α (TNF-α) was found to be closely associated with lymphatic cancer metastasis. However, the mechanism through which TNF-α regulates lymphatic metastasis in cervical cancer remains unclear. In this study, cervical cancer cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with or without TNF-α for 48 h, and then the corresponding conditional medium (CM-TNF-α or CM) was collected. The level of vascular endothelial growth factor (VEGFC) in the corresponding CM was then detected using an enzyme-linked immunosorbent assay (ELISA). Next, human lymphatic endothelial cells (HLECs) were cultured in CM-TNF-α or CM for 48 h. Cell viability was measured using the cell counting kit-8 (CCK-8) assay, and angiogenesis was detected using a tube formation assay. Subsequently, the expressions of AKT, p-AKT, ERK, and p-ERK in HLECs were detected using western blotting. In addition, to further investigate the effect of TNF-α on the progression of cervical cancer, a C33A subcutaneous xenograft model was established in vivo. We found that TNF-α significantly stimulated cervical cancer cells to secrete VEGFC. Additionally, the CM collected from the TNF-α-treated cervical cancer cells notably promoted the proliferation, migration, and angiogenesis of HLECs; however, these changes were reversed by MAZ51, a VEGFR3 inhibitor. Moreover, TNF-α obviously elevated D2-40 and VEGFC protein expressions in tumor tissues, promoting lymphangiogenesis and lymphatic metastasis in vivo. Meanwhile, TNF-α markedly upregulated p-AKT and p-ERK expressions in tumor tissues, whereas these changes were reversed by MAZ51. Collectively, TNF-α could promote tumorigenesis, lymphangiogenesis, and lymphatic metastasis in vitro and in vivo in cervical cancer via activating VEGFC-mediated AKT and ERK pathways. These results may provide new directions for the treatment of cervical cancer.

Association of high insulin receptor expression with poor prognosis in patients with breast cancer.

The aim of this study was to investigate the expression of insulin receptor (IR) in the blood vessels of patients with breast cancer (BC) with or without type 2 diabetes mellitus (DM2) and its relationship with histopathological features of BC tissues and patient prognosis. A total of 124 patients with BC diagnosed and treated at The Affiliated Hospital of Putian University between January 2018 and January 2019 were eligible for this study. According to the presence or absence of DM2, they were then divided into 2 groups: patients with BC and DM2 (DBC group, n=26) and patients with BC and without DM2 (BC group, n=98). The expression of IR in the cancer and adjacent tissues was detected using immunohistochemistry. The patients were followed up for 1 year. Kaplan-Meier analysis was used to compute the overall survival (OS) of the patients with BC. Furthermore, Cox regression was employed to investigate the correlation of IR expression with DM2, pathological tissue, TNM stage, and OS. IR expression in cancer tissues (34.7%) was significantly higher than that in adjacent normal tissues (15.3%). Among cancer tissues, IR was highly expressed in DBC tissues (57.7%) compared with BC tissues (28.6%). IR was also highly expressed in patients with tumor infiltration and lymphatic metastasis. Its expression was significantly correlated with T stage and N stage, but not with M stage. In addition, patients with high IR expression had significantly lower survival than did those with low IR expression. Moreover, univariate and multivariate Cox regression analysis indicated that tumor infiltration, lymphatic metastasis, tumor size, T stage, and high IR expression were independent risk factors for BC prognosis. High IR expression was associated with poor prognosis of patients with BC. The expression of IR may be a promising indicator to assess the survival of patients with BC.