Aggressive Clinicopathological Features Research Articles

Association Between the Presence of Female-Specific Tumors and Aggressive Clinicopathological Features in Papillary Thyroid Cancer: A Retrospective Analysis of 9,822 Cases

ObjectiveTo investigate the association between the presence of female-specific tumors and aggressive clinicopathological features in papillary thyroid cancer (PTC).MethodsThis study retrospectively analyzed 9,822 female cases between June 2008 and December 2017. Odds ratios and corresponding 95% confidence intervals were calculated. Findings were stratified by age and body mass index (BMI) in different models.Results1443/9822 (14.7%) patients with PTC had a female-specific tumor. Presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter (adjusted OR = 1.446, 95% CI 1.136–1.840, P = 0.003), but a protective factor against extrathyroidal extension of PTC (adjusted OR = 0.650, 95%CI 0.500–0.845, P = 0.001). Presence of a benign uterine mass was an independent risk factor for multifocal PTC (adjusted OR = 1.305, 95%CI 1.113–1.531, P = 0.001). Analyses stratified by age and BMI revealed the presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter in patients aged <36 years (adjusted OR = 1.711, 95% CI 1.063–2.754, P = 0.027), and a protective factor against extrathyroidal extension of PTC in patients aged ≥36 - <42 years (OR adjusted = 0.533, 95% CI 0.302–0.941, P = 0.030) or with a BMI ≥ 23.4 kg/m2 (BMI ≥ 23.4 to < 25.7 kg/m2, adjusted OR = 0.441, 95% CI 0.246–0.792, P = 0.006; BMI ≥25.7 kg/m2, adjusted OR = 0.558, 95% CI 0.315–0.998, P 2 = 0.045). Presence of a benign uterine mass was an independent risk factor for multifocal PTC in patients aged ≥49 years (adjusted OR = 1.397, 95% CI 1.088–1.793, P = 0.009) or with a BMI <21.5 kg/m2 (OR adjusted = 1.745, 95% CI 1.214–2.509, P = 0.003).ConclusionThe presence of a benign breast mass was an independent risk factor for a primary PTC lesion > 1 cm in diameter and a protective factor against extrathyroidal extension of PTC, while the presence of a benign uterine mass was an independent risk factor for multifocal PTC. Data from this study may help surgeons propose more personalized treatment plans when encountering patients with PTC and female-specific benign tumors.

STMN2 mediates nuclear translocation of Smad2/3 and enhances TGFβ signaling by destabilizing microtubules to promote epithelial-mesenchymal transition in hepatocellular carcinoma.

Metastasis remains the major obstacle of improving the survival of patients with hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is critical to cancer metastasis. Successful induction of EMT requires dramatic cytoskeleton rearrangement. However, the significance of microtubule (MT), one of the core components of cell cytoskeleton, in this process remains largely unknown. Here we revealed that STMN2, an important MT dynamics regulator, is barely expressed in normal live tissues but markedly up-regulated in HCCs, especially in those with early recurrence. High STMN2 expression correlates with aggressive clinicopathological features and predicts poor prognosis of HCC patients. STMN2 overexpression in HCC cells promotes EMT, invasion and metastasis in vitro and in vivo, whereas STMN2 knockdown has opposite results. Mechanistically, STMN2 modulates MTs disassembly, disrupts MT-Smad complex, and facilitates release from MT network, phosphorylation and nuclear translocation of Smad2/3 even independent of TGFβ stimulation, thereby enhancing TGFβ signaling. Collectively, STMN2 orchestrates MT disassembly to facilitate EMT via TGF-β signaling, providing a novel insight into the mechanisms underlying cancer metastasis. STMN2 is a promising prognostic biomarker and potential therapeutic target for HCC.

Elevated SYNC Expression Is Associated with Gastric Tumorigenesis and Infiltration of M2-Polarized Macrophages in the Gastric Tumor Immune Microenvironment.

Aims: To assess the expression and epigenetic regulation of Syncoilin, intermediate filament protein (SYNC) in gastric cancer tissues, and to determine its associations with clinicopathological features; immune infiltration of macrophages in tumors; and patient survival. Materials and Methods: Clinicopathological features, expression profiles, and methylation data of the SYNC gene were obtained from multi-institutional real-world public datasets. A total of 1601 samples from patients with gastric cancer were examined. The associations between clinicopathological features and SYNC expression levels were assessed by the chi-square test; survival was assessed using the Kaplan-Meier analysis. The infiltration levels of M1, 2-polarized tumor-associated macrophages (TAMs) in a gastric tumor immune microenvironment were quantified using deconvolution, and the correlation between SYNC expression level and M1, 2-polarized macrophages' infiltration was examined using the Pearson correlation test. SYNC gene methylation data were analyzed to investigate epigenetic control of its expression. Results: SYNC expression was elevated in gastric cancer tissues (p < 0.01), and was associated with a poorer overall survival (p < 0.01) and poorer postprogression survival (p = 0.01). Higher SYNC levels were significantly associated with more aggressive clinicopathological features in gastric cancer patients (p < 0.05). SYNC was also associated with the infiltration of M2-polarized TAMs in the gastric tumor immune microenvironment (p < 0.001). Hypomethylation was shown to be associated with SYNC's upregulation (p < 0.05). Conclusion: SYNC is highly expressed in gastric cancer tissues and has the potential to be a therapeutic target and to serve as a prognostic marker.

Promising role of long non-coding RNA PCAT6 in malignancies

Long non-coding RNAs (lncRNAs), a newly identified class of non-coding RNA (ncRNA), are defined as RNA molecules at least 200 nucleotides in length that are not translated into proteins. LncRNAs contribute to a wide range of biological processes and are master regulators of disease occurrence, development, and response to therapy in human malignancies. The lncRNA prostate cancer‑associated transcript 6 (PCAT6) is upregulated in various human malignancies, including lung cancer, hepatocellular carcinoma, cervical cancer, osteosarcoma, glioblastoma, colorectal cancer, breast cancer, gastric cancer, gastrointestinal stromal tumors, and pancreatic ductal adenocarcinoma. High expression of PCAT6 is closely correlated with aggressive clinicopathological characteristics and poor prognosis in cancer patients, suggesting it is an oncogenic lncRNA. PCAT6 overexpression also facilitates cell proliferation, invasion, and migration while attenuating apoptosis, indicating that it might serve as a new prognostic biomarker and therapeutic target for malignancies. Here, we discuss the molecular mechanisms, regulatory functions, and potential clinical applications of PCAT6 in cancer.

KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma.

KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRAS G12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRAS G12C-mutant lung adenocarcinoma. Patients who underwent resection of stage I-III lung adenocarcinoma and next-generation sequencing (NGS) were evaluated. Exclusion criteria were receipt of induction therapy, incomplete resection, and low-quality NGS. Mutations were classified as KRAS wild-type (KRAS wt), G12C (KRAS G12C), or non-G12C (KRAS other). DFS was compared between groups using the log-rank test; factors associated with DFS were assessed using Cox regression. Mutual exclusivity and cooccurrence, tumor clonality, and mutational signatures were assessed. In total, 604 patients were included: 374 KRAS wt (62%), 95 KRAS G12C (16%), and 135 KRAS other (22%). Three-year DFS was not different between KRAS-mutant and KRAS wt tumors. However, 3-year DFS was worse in patients with KRAS G12C than KRAS other tumors (log-rank P = 0.029). KRAS G12C tumors had more lymphovascular invasion (51% vs. 37%; P = 0.032) and higher tumor mutation burden [median (interquartile range), 7.0 (5.3-10.8) vs. 6.1 (3.5-9.7); P = 0.021], compared with KRAS other tumors. KRAS G12C mutation was independently associated with worse DFS on multivariable analysis. Our DFS findings were externally validated in an independent The Cancer Genome Atlas cohort. KRAS G12C mutations are associated with worse DFS after complete resection of stage I-III lung adenocarcinoma. These tumors harbor more aggressive clinicopathologic and genomic features than other KRAS-mutant tumors. We identified a high-risk group for whom KRAS G12C inhibitors may be investigated to improve survival.

Abstract PS5-45: The impact of progesterone receptor negativity on oncologic outcomes in estrogen receptor positive breast cancer

Abstract BACKGROUND: Estrogen receptor (ER) status provides invaluable prognostic and therapeutic information in breast cancer (BC). When clinical decision making is driven by ER status, the value of assessing progesterone receptor (PgR) status is less certain. AIM: To describe the clinicopathologic features of ER positive (ER+) /PgR negative (PgR-) BC and to determine the effect of PgR negativity on oncologic outcomes in ER+ disease.METHODS: Consecutive female patients with ER+ BC managed in a single institution between 2005-2015 were included. Clinicopathological features of PgR- BC were determined. Factors associated with PgR- disease were assessed using binary logistic regression. Oncological outcome was assessed using Kaplan-Meier curves and Cox regression analysis.RESULTS: 2660 patients were included with a median age of 59.6±13.3 years (21-99). Median follow-up was 97.2 months (3.0-181.2). 2208 cases were PgR+ (83.0%) and 452 were PgR- (17.0%). Being postmenopausal (OR:1.656, 95% Confidence interval (CI):1.249-2.195, P&amp;lt;0.001), presenting with symptoms (OR:1.712, 95% CI:1.302-2.249, P&amp;lt;0.001), invasive ductal subtype (OR:1.514, 95% CI:1.166-1.966, P=0.002) and grade 3 tumours (OR:2.198, 95% CI:1.683-2.870, P&amp;lt;0.001) were all associated with PgR- status. In patients receiving neoadjuvant chemotherapy (n=308), pathological complete response rates were 10.1% (25/247) in patients with PgR+ disease, versus 18.0% in those with PgR- disease (11/61) (P=0.050). PgR negativity independently predicted worse disease-free (HR:1.632, 95%CI:1.209-2.204, P=0.001) and overall survival (OS) (HR:1.774, 95%CI:1.324-2.375, P&amp;lt;0.001), as well as worse OS in ER+/HER2- disease (P=0.004). CONCLUSIONS: In ER+ disease, PgR- tumours have more aggressive clinicopathological features and worse oncological outcomes. Neoadjuvant and adjuvant therapeutic strategies should be tailored according to PgR status. Citation Format: Matthew G Davey, Éanna J Ryan, Padraig J Folan, Niamh O'Halloran, Michael R Boland, Michael Kevin Barry, Karl J Sweeney, Carmel M Malone, Ray J McLaughlin, Michael J Kerin, Aoife J Lowery. The impact of progesterone receptor negativity on oncologic outcomes in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-45.

CD30-Positive Anaplastic Variant of Diffuse Large B-cell Lymphoma: Frequency and Association With Clinicopathological Parameters.

IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma and is the most common type of non-Hodgkin's lymphoma (NHL) worldwide. The World Health Organization (WHO) classification of hematopoietic tumors has recognized three morphological variants of DLBCL: centroblastic, immunoblastic, and anaplastic. Some studies have shown that the anaplastic variant of DLBCL is associated with aggressive clinicopathological features. Anaplastic DLBCL is rare, and the clinicopathological characteristics of this subtype of DLBCL are not widely studied in our population. Therefore, in this study, we evaluated the frequency of the anaplastic variant of DLBCL and its association with other clinicopathological parameters.MethodsA retrospective study was conducted in the Department of Histopathology at the Liaquat National Hospital and Medical College over a period of six years, from January 2015 to December 2020. All cases diagnosed as DLBCL based on morphology and immunohistochemical (IHC) profile were included in the study. The diagnosis of anaplastic DLBCL was rendered based on morphology (large bizarre pleomorphic cells in a cohesive or sheet-like growth pattern), combined with CD30 IHC expression.ResultsThe mean age of the patients was 52.90 ±16.42 years, and the mean Ki67 index was 73.18 ±16.52%. Of the 220 cases of DLBCL, 47.3% cases were germinal center B-cell (GCB) subtype, and 59.1% cases were nodal. BCL-2, BCL-6, MUM1, c-MYC, and CD10 positivity were noted in 60%, 45.5%, 40.9%, 44.1, and 38.6% cases, respectively. Only 14 cases (6.4%) were recognized as anaplastic variants of DLBCL according to the previously defined criterion. The only significant association of anaplastic-variant DLBCL was noted with a lack of BCL-2 expression. No significant association of anaplastic-variant DLBCL was noted with age, gender, Ki67 index, DLBCL subtype, or any other IHC marker expression.ConclusionWe found a low frequency of the anaplastic variant of DLBCL in our study. No significant association of this DLBCL variant was noted with any of the clinicopathological parameters, except for the lack of BCL-2 expression. Alternatively, from a pathological perspective, it is important to recognize this variant of DLBCL as it often mimics other CD30-positive lymphoma and undifferentiated carcinoma.

Prognostic and Clinicopathological Significance of Circular RNA circ-ITCH Expression in Cancer Patients: A Meta-analysis.

Circular RNAs are a class of RNAs with a covalently closed configuration, and several members of them have been reported to be capable of regulating various biological processes and predicting the outcome of disease. Among them, circular RNA circ-ITCH has been identified to be aberrantly expressed and associated with disease progression in diverse cancers. However, the correlation of circ-ITCH expression with clinicopathological features, as well as the prognosis of cancers, remains inconclusive. Therefore, a meta-analysis was performed to investigate the clinical significance of circ-ITCH in cancers by systematically summarizing all eligible literatures. Up to August 31, 2020, relevant articles were searched in PubMed, Web of Science, Cochrane library, Embase, CNKI, and Wanfang databases. Pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. A total of 1604 patients from 14 studies were included in this meta-analysis. The results showed that cancer patients with low circ-ITCH expression were more susceptible to develop lymph node metastasis (OR = 2.25, 95% CI: 1.67-3.02, p ≤ 0.01), larger tumor size (OR = 3.01, 95% CI: 2.01-4.52, p ≤ 0.01), advanced TNM stage (OR = 2.82, 95% CI: 1.92-4.14, p ≤ 0.01), and poor overall survival (OS) (HR = 2.45, 95% CI: 2.07–2.90, p ≤ 0.01, univariate analysis; HR = 2.69, 95% CI: 1.82-3.96, p ≤ 0.01, multivariate analysis). Thus, low circ-ITCH expression was significantly associated with aggressive clinicopathological features and unfavorable outcome in various cancers. Therefore, circ-ITCH may serve as a molecular therapy target and a prognostic marker in human cancers.

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers.

Several clinical trials are investigating the use of immune-targeted therapy with Programmed death ligand-1 (PD-L1) inhibitors for colorectal cancer (CRC), with promising results for patients with mismatch repair (MMR) deficiency or metastatic CRC. However, the prognostic significance of PD-L1 expression in CRC is controversial and such data are lacking in CRC from Middle Eastern ethnicity. We carried out this large retrospective study to investigate the prognostic and clinico-pathological impact of PD-L1 expression in Middle Eastern CRC using immunohistochemistry. A total of 1148 CRC were analyzed for PD-L1 expression. High PD-L1 expression was noted in 37.3% (428/1148) cases and was correlated with aggressive clinico-pathological features such as high malignancy grade (p < 0.0001), larger tumor size (p = 0.0007) and mucinous histology (p = 0.0005). Interestingly, PD-L1 expression was significantly higher in patients exhibiting MMR deficiency (p = 0.0169) and BRAF mutation (p = 0.0008). Furthermore, the expression of PD-L1 was found to be an independent marker for overall survival (HR = 1.45; 95% CI = 1.06–1.99; p = 0.0200). In conclusion, the results of this study indicate that PD-L1 expression could be a valid biomarker for poor prognosis in Middle Eastern CRC patients. This information can help in decision-making for anti-PD-L1 therapy in Middle Eastern CRC, especially for patients with MMR deficient tumors.

Breast Cancer in Young Women: A Clinicopathological Hospital-based Descriptive Study from Kurdistan, Iraq

Background: Young women with breast cancer have been reported to present more aggressive clinical and pathological features, requiring more treatment options compared with older patients. Our objective was to investigate the clinicopathological features of breast cancer in our local young women. Method: We conducted an observational descriptive study on 100 young women (age ≤ 40) with breast cancer. The subjects were taken care of, at a single tertiary cancer facility, from mid-2007 to mid-2014. We reviewed the clinicopathological profiles and therapeutic strategies. Results: Ratio of breast cancer in young women was about 13% of all breast cancer patients. The mean age of the patients was 35 years ± 4SD. 56% of the patients had grade III tumors and 46% were in stage III. Hormonal receptors were positive in 70%, while HER2 was positive in 26%. 70% of the patients underwent modified radical mastectomy, 96% received chemotherapy, and 70% received radiotherapy and required hormonal therapy. Conclusion: This review showed that breast cancer in our local young women was largely diagnosed at advanced stages with more aggressive clinico-pathological features. Moreover, most of the patients received more aggressive treatment options. Therefore, physicians should pay a close attention to breast lumps in young women.

The 14-3-3σ protein promotes HCC anoikis resistance by inhibiting EGFR degradation and thereby activating the EGFR-dependent ERK1/2 signaling pathway.

Resistance to anoikis, cell death due to matrix detachment, is acquired during tumor progression. The 14-3-3σ protein is implicated in the development of chemo- and radiation resistance, indicating a poor prognosis in multiple human cancers. However, its function in anoikis resistance and metastasis in hepatocellular carcinoma (HCC) is currently unknown.Methods: Protein expression levels of 14-3-3σ were measured in paired HCC and normal tissue samples using western blot and immunohistochemical (IHC) staining. Statistical analysis was performed to evaluate the clinical correlation between 14-3-3σ expression, clinicopathological features, and overall survival. Artificial modulation of 14-3-3σ (downregulation and overexpression) was performed to explore the role of 14-3-3σ in HCC anoikis resistance and tumor metastasis in vitro and in vivo. Association of 14-3-3σ with epidermal growth factor receptor (EGFR) was assayed by co-immunoprecipitation. Effects of ectopic 14-3-3σ expression or knockdown on EGFR signaling, ligand-induced EGFR degradation and ubiquitination were examined using immunoblotting and co-immunoprecipitation, immunofluorescence staining, and flow cytometry analysis. The levels of EGFR ubiquitination, the interaction between EGFR and 14-3-3σ, and the association of EGFR with c-Cbl after EGF stimulation, in 14-3-3σ overexpressing or knockdown cells were examined to elucidate the mechanism by which 14-3-3σ inhibits EGFR degradation. Using gain-of-function or loss-of-function strategies, we further investigated the role of the EGFR signaling pathway and its downstream target machinery in 14-3-3σ-mediated anoikis resistance of HCC cells.Results: We demonstrated that 14-3-3σ was upregulated in HCC tissues, whereby its overexpression was correlated with aggressive clinicopathological features and a poor prognosis. In vitro and in vivo experiments indicated that 14-3-3σ promoted anoikis resistance and metastasis of HCC cells. Mechanistically, we show that 14-3-3σ can interact with EGFR and significantly inhibit EGF-induced degradation of EGFR, stabilizing the activated receptor, and therefore prolong the activation of EGFR signaling. We demonstrated that 14-3-3σ downregulated ligand-induced EGFR degradation by inhibiting EGFR-c-Cbl association and subsequent c-Cbl-mediated EGFR ubiquitination. We further verified that activation of the ERK1/2 pathway was responsible for 14-3-3σ-mediated anoikis resistance of HCC cells. Moreover, EGFR inactivation could reverse the 14-3-3σ-mediated effects on ERK1/2 phosphorylation and anoikis resistance. Expression of 14-3-3σ and EGFR were found to be positively correlated in human HCC tissues.Conclusions: Our results indicate that 14-3-3σ plays a pivotal role in the anoikis resistance and metastasis of HCC cells, presumably by inhibiting EGFR degradation and regulating the activation of the EGFR-dependent ERK1/2 pathway. To our best knowledge, this is the first report of the role of 14-3-3σ in the anoikis resistance of HCC cells, offering new research directions for the treatment of metastatic cancer by targeting 14-3-3σ.

Alternative lengthening of telomeres in pancreatic neuroendocrine tumors is associated with more aggressive clinicopathologic features and increased risk of recurrence

Alternative lengthening of telomeres in pancreatic neuroendocrine tumors is associated with more aggressive clinicopathologic features and increased risk of recurrence

The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

ABSTRACT The effect of anti-programmed cell death 1 (PD-1) antibody in Epstein-Barr virus-associated gastric cancer (EBVaGC) was debatable, and no predictive biomarkers for efficacy have been reported. Public reports on anti-PD-1 antibody monotherapy-treated EBVaGC with available programmed death ligand-1 (PD-L1) expression status were summarized and analyzed. Relevance with clinicopathologic characteristics of PD-L1 expression by immunohistochemistry was analyzed in 159 patients diagnosed with EBVaGC. Relevance with genomic transcriptome and mutation profile of PD-L1 status in EBVaGC was assessed with three datasets, the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO) GSE51575, and GSE62254. Based on the data from 8 reports, patients with positive PD-L1 expression (n = 30) had significantly superior objective response rate (ORR) than patients with negative PD-L1 expression (n = 9) (63.3% vs. 0%, P = .001) in EBVaGC receiving anti-PD-1 antibody monotherapy. PD-L1 positivity was associated with less aggressive clinicopathological characteristics and was an independent predictor for a longer disease-free survival (hazard ratio [HR] and 95% CI: 0.45 [0.22–0.92], P = .03) and overall survival (HR and 95% CI: 0.17 [0.06–0.43], P < .001). Analysis of public EBVaGC transcriptome and mutation datasets revealed enhanced immune-related signal pathways in PD-L1high EBVaGC and distinct mutation patterns in PD-L1low EBVaGC. PD-L1 positivity indicates a subtype of EBVaGC with ‘hot’ immune microenvironment, lower aggressiveness, better prognosis, and higher sensitivity to anti-PD-1 immunotherapy.

HIF-1-induced mitochondrial ribosome protein L52: a mechanism for breast cancer cellular adaptation and metastatic initiation in response to hypoxia.

Background: Hypoxia is a hallmark of the physical microenvironment of solid tumors. As a key factor that regulates tumor development and progression, hypoxia can reprogram the expression of multiple genes, whose biological function and molecular mechanism in cancer remain largely unclear. The mitochondrial ribosome protein family consists of nuclear-encoded mitochondrial proteins that are responsible for protein synthesis in the mitochondria.Methods: A high-throughput RNA sequencing assay was carried out to identify differentially expressed mRNAs between breast cancer tissues and adjacent normal tissues as well as breast tumors with metastasis and those without metastasis. Our clinical samples and TCGA database were analyzed to observe the clinical value of mitochondrial ribosome protein L52 (MRPL52) in human breast cancer. Potent hypoxia response elements in the promoter region of MRPL52 were identified and validated by chromatin immunoprecipitation and luciferase reporter assays. Functional experiments were performed using breast cancer cell lines with MRPL52 ectopic expression and knockdown cultured in a 20% or 1% O2 environment.Results: MRPL52 expression was upregulated in human breast cancer and was significantly associated with aggressive clinicopathological characteristics and a higher metastatic risk of breast cancer patients. We found that the overexpression of MRPL52 in breast cancer is induced by hypoxia-inducible factor-1 in response to hypoxic exposure. The role of MRPL52 in suppressing apoptosis and promoting migration and invasion of hypoxic breast cancer cells was demonstrated by our experimental evidence. Mechanistically, MRPL52 promoted PTEN-induced putative kinase 1 /Parkin-dependent mitophagy to remove oxidatively damaged mitochondria and prevent uncontrolled reactive oxygen species (ROS) generation, thus repressing activation of the mitochondrial apoptotic cascade. Additionally, MRPL52 augmented epithelial-mesenchymal transition, migration and invasion of hypoxic breast cancer cells by activating the ROS-Notch1-Snail signaling pathway. Benefited from this bidirectional regulatory mechanism, MRPL52 is responsible for maintaining ROS levels in a window that can induce tumorigenic signal transduction without causing cytotoxicity in hypoxic breast cancer cells.Conclusions: This work elucidates the molecular mechanism by which MRPL52 mediates hypoxia-induced apoptotic resistance and metastatic initiation of breast cancer, and provides new insights into the interplay between cancer and the tumor microenvironment.

SCARA5 inhibits gastric cancer progression via epithelial-mesenchymal transition suppression.

Scavenger receptor class A member 5 (SCARA5) has been reported to be implicated in several types of cancer. However, its biological roles and mechanism of SCARA5 in gastric cancer (GC) have not been elucidated. In the present study, SCARA5 expression was found to be downregulated in GC which was associated with promoter methylation. The protein level of SCARA5 was negatively associated with aggressive clinicopathological characteristics, as well as poor prognosis. Moreover, SCARA5 overexpression markedly suppressed the growth, migration and invasion of GC cell lines in vitro. Furthermore, upregulation of SCARA5 inhibited gastric tumor growth and metastasis in a xenograft model. Mechanistic analysis revealed that SCARA5 suppressed the migration and invasion of GC cells via inhibiting epithelial-mesenchymal transition (EMT) and inactivating MMP-2 and MMP-9. Taken together, these results demonstrated that SCARA5 might play vital roles in the GC genesis and progression and could serve as a potential biomarker for diagnosis and therapeutic target of GC.

MicroRNA-20a Targeting LASS2 Promotes the Proliferation, Invasiveness and Migration of Bladder Cancer.

Abnormal expression of miR 20a is reported in various types of malignancy neoplasms. However, its function is not consistent in different tumors. This study aims to explore the potential functions of miR 20a and its underlying mechanisms in bladder cancer. Ninety-six patients diagnosed with bladder cancer were recruited into the study. The expression levels of miR-20a in bladder cancer samples and adjacent non-tumor samples were investigated by qRT-PCR. Wound healing, CCK8, and transwell migration assays were carried out for determining the functions of miR20a. Bioinformatics analysis was used for predicting the downstream gene of miR-20a. Western blot, qRT-PCR, and fluorescent reporter assays were used to verify the target gene. MiR-20a was significantly increased in bladder cancer tissues, and its rising level was closely correlated with histological grade, clinical stage, recurrence and metastasis in bladder cancer. Exogenous upregulation of miR-20a expression obviously enhanced the aggressive biological functions of bladder cancer in vitro. LASS2 was verified to be a target gene of miR-20a. Moreover, miR-20a can negatively regulate LASS2 at protein and mRNA levels. Increasing miR-20a is closely related to aggressive clinicopathological features. MiR 20a plays an oncogenic role in bladder cancer, which contributes to target LASS2 directly.

Diagnostic Value of Serum Cytokeratin 18, Carcinoembryonic Antigen, and Thyroglobulin in Patients with Papillary Thyroid Carcinoma.

The current study aims to explore the expression and diagnostic value of cytokeratin 18 (CK) in patients with papillary thyroid carcinoma (PTC). Patients diagnosed with thyroid tumor, including 127 cases of PTC and 60 cases of benign tumors and 50 healthy controls were included. Serum CK 18, carcinoembryonic antigen (CEA) and thyroglobulin (Tg) were detected using enzyme-linked immunosorbent assay (ELISA). The diagnostic value of serum CK 18, CEA, and Tg for PTC was analyzed by receiver-operating characteristic (ROC) curve. We showed novel data that the level of serum CK 18 was higher in PTC patients than that in controls. Upregulation of serum CK 18 correlated with aggressive clinicopathologic characteristics of PTC, including lymph node metastasis, high ASA risk classification, advanced TNM stage, and larger tumor size. Furthermore, serum CEA and Tg levels of thyroid cancer patients were significantly higher than those of the benign group. More importantly, the AUC-ROC of combined serum CEA, Tg, and CK 18 was higher than that of CEA, Tg, and CK 18 alone, indicating the combination of serum CEA, Tg, and CK 18 significantly improved the diagnostic efficiency in PTC patients. Altogether, combined use of serum CK 18, Tg, and CEA may be a promising biomarker in screening benign and malignant thyroid tumors.

Prune-1 drives polarization of tumor-associated macrophages (TAMs) within the lung metastatic niche in triple-negative breast cancer

SummaryM2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.

Elevated TUBA1A Might Indicate the Clinical Outcomes of Patients with Gastric Cancer, Being Associated with the Infiltration of Macrophages in the Tumor Immune Microenvironment.

TUBA1A belongs to the tubulin superfamily, and its role in gastric cancer (GC) remains unclear. This study assessed the expression and effect of TUBA1A in GC, as well as its association with survival and clinicopathological features. Gene set enrichment analysis (GSEA) results revealed that high TUBA1A expression was associated with multiple pathways, including those that contributed to the infiltration of macrophages in the tumor microenvironment. Since increased infiltration of macrophages can lead to oxaliplatin resistance, we analyzed the association between TUBA1A, the infiltration of macrophages to the tumor microenvironment, and the inhibitory concentration 50% (IC50) of oxaliplatin. In addition, we analyzed the possible epigenetic regulation mechanism. A total of 1,881 samples, including 1,618 patients with GC and 263 normal samples, were examined. The associations between clinicopathological features and TUBA1A were assessed by chi-square test, survival was assessed by Kaplan-Meier analysis, and gene set enrichment analysis (GSEA) was performed to explore the potential mechanisms. The associations between TUBA1A and immune infiltration of M0-, M1-, and M2- polarized macrophages were examined by applying deconvolution's quantification and Pearson's correlation analysis. The association of TUBA1A with the IC50 of oxaliplatin was analyzed by Pearson correlation test. The mechanisms of TUBA1A dysregulation were studied by analyzing methylation data. A single-cell TUBA1A mRNA expression map of the stomach was drawn from the analysis of stomach single-cell RNA sequencing data that included more than 13,000 single cells of 17 stomach cell types. TUBA1A expression was elevated in GC (p<0.01) and indicated poorer overall survival (p<0.001), first progression survival (p<0.001), and post-progression survival (p<0.01). High TUBA1A expression was significantly correlated with more aggressive clinicopathological features of GC patients (p<0.001). Elevated TUBA1A contributes to the infiltration of macrophages to the tumor microenvironment (p<0.001) and increased the IC50 of oxaliplatin in vitro (p<0.05), while hypomethylation was shown to contribute to the upregulation of TUBA1A (p<0.05). TUBA1A might be a potential prognostic marker and therapeutic target in GC. TUBA1A is significantly associated with the infiltration of M2-polarized macrophages in GC, and the IC50 of oxaliplatin. Hypomethylation contributes to the upregulation of TUBA1A in GC.

BRAF V600E mutation correlates with aggressive clinico-pathological features but does not influence tumor recurrence in papillary thyroid carcinoma-10-year single-center results.

BRAF V600E mutation is common in papillary thyroid carcinoma (PTC) but its prognostic value and influence on tumor recurrence is controversial. We investigated if BRAF V600E mutation influences tumor behavior and recurrence, and if it can be used as surrogate parameter in PTC. In a single center retrospective study with a median follow-up of 5 years, incidence of BRAF V600E mutation in 186 PTC specimens from 2007-2016 was investigated. Tumor outcome parameters including TNM status, multifocal and invasive growth and tumor recurrence rate were examined. In 98 specimens (52.7%) a BRAF V600E mutation (BRAF+), and in 88 specimens (47.3%) no mutation (BRAF-) was detected. There was no gender specific difference. BRAF+ patients were significantly older (mean 5.6 years; P=0.011). BRAF+ tumors were significantly smaller (14.4 vs. 18.3 mm; P=0.018), and more often showed a multifocal (30.6% vs. 17%; P=0.031) and extracapsular tumor growth pattern (pT3b and pT4a; BRAF+ 22.4% vs. BRAF- 10.2%; P=0.026). Although lymph node-status did not differ in both groups, BRAF+ showed a higher infiltration rate of the lateral lymph node compartment (12.2% vs. 5.7%; P=n.s.). Distant metastases occurred only in BRAF+ (3.1% vs. 0%). There was no significant difference in terms of tumor recurrence rate. Results regarding the incidence of malignant lymph nodes, tumor growth pattern and tumor multifocality suggest a more aggressive tumor behavior in BRAF+ PTC but this fact does not affect tumor recurrence rate in a five year follow up period. Therefore, the postoperative role of BRAF V600E mutation remains unclear, and a general change of operative procedure and radicality cannot be recommended based on BRAF status alone.