Advanced Lymph Node Metastasis Research Articles

Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Cancer Progression via Activating PI3K/AKT/mTOR Pathway.

Aim The aim of this study was to investigate the effect and underlying pathway of pyrroline-5-carboxylate reductase-2 (PYCR2) on colorectal cancer (CRC). Methods The Cancer Genome Atlas (TCGA) database was used to analyze PYCR2 expression levels and clinical information. Cell proliferation was evaluated using colony forming and EdU assay. Cell apoptosis rate was determined using flow cytometry. Cell migration and invasion were measured by performing a Transwell assay, and PYCR2, MMP-2, MMP-9, Bax, cleaved caspase-3, Bcl-2, cleaved PARP, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR protein levels were detected by Western blot. Results A review of the TCGA database revealed that PYCR2 was highly expressed in CRC patients and that high PYCR2 expression was associated with advanced stage, adenocarcinoma, nodal metastasis, and poor survival rate. Moreover, PYCR2 knockdown reduced cell viability, proliferation, migration, and invasion and increased apoptosis. Additionally, PYCR2 knockdown increased Bax, cleaved caspase-3, and cleaved PARP levels and decreased Bcl-2, MMP-2, MMP-9, p-PI3K, p-AKT, and p-mTOR levels in CRC cells. Effects of silencing PYCR2 on proliferation, migration, invasion, apoptosis, and the PI3K/AKT/mTOR pathway in CRC cells were all reversed using a PI3K activator (740Y-P). Conclusion PYCR2 was highly expressed in CRC, and its knockdown suppressed CRC tumorigenesis via inhibiting the activation of PI3K/AKT/mTOR pathway. This finding provides a new theoretical foundation for the treatment of CRC.

Pattern of placental alkaline phosphatase (PLAP) expression in human tumors: a tissue microarray study on 12,381 tumors.

Placental alkaline phosphatase (PLAP) is commonly expressed at high levels in testicular germ cell tumors. PLAP immunohistochemistry (IHC) is thus often used to confirm this diagnosis, especially in cases of putative metastasis. However, other tumors can also express PLAP. To comprehensively determine PLAP expression in normal and tumor tissue, a tissue microarray containing 16,166 samples from 131 different tumor types and subtypes as well as 608 samples from 76 different normal tissue types was analyzed by IHC. Moderate to strong PLAP positivity was found in 27 (21%) of 131 different tumor types including seminoma (96%), embryonal carcinoma (85%), and yolk sac tumors of the testis (56%); endometrioid carcinoma of the endometrium (28%) and the ovary (20%); gastric adenocarcinoma (22%); serous carcinoma (not otherwise specified) of the ovary (17%) and the uterus (11%); adenocarcinoma of the ampulla of Vater (15%); carcinosarcoma of the ovary (11%) and the uterus (8%); esophageal adenocarcinoma (10%); invasive urothelial carcinoma (4%); cholangiocarcinoma (2%); and adenocarcinoma of the lung (1%). Low‐level PLAP immunostaining, often involving only a small fraction of tumor cells, was seen in 21 additional tumor entities. The clinical significance of PLAP expression may vary between tumor types as high PLAP expression was linked to advanced pathological tumor stage (p = 0.0086), nodal metastasis (p = 0.0085), and lymphatic (p = 0.0007) and blood vessel invasion (p = 0.0222) in colorectal cancer, but to low pathological tumor stage in endometrial cancer (p = 0.0043). In conclusion, our data identify several tumor entities that can show PLAP expression at comparable levels to testicular germ cell tumors. These tumor entities need to be considered in cases of PLAP‐positive metastasis. Low‐level PLAP expression can be found in various other tumor entities and should generally not be viewed as a strong argument for germ cell neoplasia.

PERINEURAL INVASION IN ORAL SQUAMOUS CELL CARCINOMA: INCIDENCE, CLINICAL IMPACT AND MOLECULAR INSIGHT

<h3>Background</h3> Perineural invasion (PNI) has been associated with poor prognosis in oral squamous cell carcinoma (OSCC). Nerve growth factor (NGF) and its receptor tyrosine kinase A (TrkA) may play a role in PNI in OSCC. <h3>Objective</h3> To characterize the incidence and prognostic correlation of PNI in OSCC and to determine whether NGF and TrkA expressions could be used as biological markers for PNI in OSCC. <h3>Methods</h3> A retrospective review of pathology reports of 430 patients with OSCC treated from 1992 to 2014 in Tayside, Scotland, and followed for 5 years or until death was undertaken. The expression of NGF and TrkA was assessed with immunohistochemistry in 132 tissue sections of OSCC. <h3>Results</h3> PNI was identified in 17.4% of OSCC. High expression of NGF and TrkA was seen in 84% and 92% of OSCC, respectively. PNI-positive OSCC expressed NGF and TrkA with greater frequency than PNI-negative OSCC (<i>P</i> < .05). PNI and high expression of NGF were associated significantly with pain in OSCC (<i>P</i> < .05). PNI-positive OSCC and high NGF/TrkA expression exhibited a greater potential for lymphovascular invasion and depth of invasion >4 mm (<i>P</i> < .05). PNI was significantly associated with advanced size, nodal metastasis, poor differentiation, and stage IV tumors (<i>P</i> < .05). PNI correlated significantly with disease-specific survival in OSCC (<i>P</i> < .05). <h3>Conclusions</h3> Higher level of expression of NGF and TrkA many predict PNI and therefore may be considered as biological markers for PNI in OSCC. Pain could be a predictive for PNI and NGF overexpression. PNI and NGF expression can predict the aggressiveness and prognosis of OSCC.

Hsa_circ_0031787 promotes cell proliferation and invasion in colorectal cancer.

Circular RNA (circRNA) has been found to be involved in regulating tumor development. However, the roles and underlying mechanisms of circRNA in colorectal cancer (CRC) development remain unclear. In this study, we investigated the effects of hsa_circ_0031787 on CRC.a METHODS: Aberrant circRNA expression was explored by the Gene Expression Omnibus (GEO) database, and hsa_circ_0031787 was selected for further study. Hsa_circ_0031787 expression was determined in CRC tissues and cell lines by qRT-PCR. Cell proliferation was measured by Edu and colony formation assays. Cell invasion was tested by Transwell assays. Hsa_circ_0031787 expression levels in CRC were significantly increased and correlated with advanced TNM stage and lymph node metastasis in CRC patients. Functional assays showed that hsa_circ_0031787 suppression reduced CRC cell proliferation and invasion in vitro and reduced tumor growth in vivo. Furthermore, hsa_circ_0031787 suppression reduced activation ofthe Wnt/β-catenin axis in CRC. Our results showed that hsa_circ_0031787 may function as an oncogenic circRNA in CRC progression, thus providing a new potential therapeutic target.

E-Cadherin expression in human tumors: a tissue microarray study on 10,851 tumors

BackgroundThe E-Cadherin gene (CDH1, Cadherin 1), located at 16q22.1 encodes for a calcium-dependent membranous glycoprotein with an important role in cellular adhesion and polarity maintenance.MethodsTo systematically determine E-Cadherin protein expression in normal and cancerous tissues, 14,637 tumor samples from 112 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format.ResultsE-Cadherin was strongly expressed in normal epithelial cells of most organs. From 77 tumor entities derived from cell types normally positive for E-Cadherin, 35 (45.5%) retained at least a weak E-Cadherin immunostaining in ≥99% of cases and 61 (79.2%) in ≥90% of cases. Tumors with the highest rates of E-Cadherin loss included Merkel cell carcinoma, anaplastic thyroid carcinoma, lobular carcinoma of the breast, and sarcomatoid and small cell neuroendocrine carcinomas of the urinary bladder. Reduced E-Cadherin expression was linked to higher grade (p = 0.0009), triple negative receptor status (p = 0.0336), and poor prognosis (p = 0.0466) in invasive breast carcinoma of no special type, triple negative receptor status in lobular carcinoma of the breast (p = 0.0454), advanced pT stage (p = 0.0047) and lymph node metastasis in colorectal cancer (p < 0.0001), and was more common in recurrent than in primary prostate cancer (p < 0.0001). Of 29 tumor entities derived from E-Cadherin negative normal tissues, a weak to strong E-Cadherin staining could be detected in at least 10% of cases in 15 different tumor entities (51.7%). Tumors with the highest frequency of E-Cadherin upregulation included various subtypes of testicular germ cell tumors and renal cell carcinomas (RCC). E-Cadherin upregulation was more commonly seen in malignant than in benign soft tissue tumors (p = 0.0104) and was associated with advanced tumor stage (p = 0.0276) and higher grade (p = 0.0035) in clear cell RCC, and linked to advanced tumor stage (p = 0.0424) and poor prognosis in papillary RCC (p ≤ 0.05).ConclusionE-Cadherin is consistently expressed in various epithelial cancers. Down-regulation or loss of E-Cadherin expression in cancers arising from E-Cadherin positive tissues as well as E-Cadherin neo-expression in cancers arising from E-Cadherin negative tissues is linked to cancer progression and may reflect tumor dedifferentiation.

Correlation of microRNA-367 in the clinicopathologic features and prognosis of breast cancer patients.

Breast cancer (BC) is a malignant tumor originating from cells of the breast. Notably, microRNAs have been recognized as biomarkers of BC metastasis. The present study is designed to evaluate the association between microRNA (miR)-367 expression and BC with the variance of clinicopathologic features and prognosis.Initially, 63 BC patients were allocated in the BC group, while the other 40 healthy volunteers were recruited as the control group. miR-367 expression in the serum of patients and healthy controls was detected using real-time polymerase chain reaction. Furthermore, the relation between miR-367 in serum and clinicopathologic features and prognosis of BC patients was accessed.miR-367 expression in serum of the BC group was evidently lower than that in the control group (all P < .001). Besides, miR-367 underexpression in the BC group was closely associated with the variance in tumor nodes metastasis advanced stage, tumor diameter, and lymph node metastasis of BC (all P < .001). In addition, compared with the control group, poorly expressed miR-367 BC group had short period of disease-free survival and overall survival (all P < .001).Our study demonstrated that miR-367 expression is associated with BC clinicopathologic features and prognosis. This investigation may offer new insight for BC treatment.

CMTM4 regulates epithelial-mesenchymal transition and PD-L1 expression in head and neck squamous cell carcinoma.

The epithelial-mesenchymal transition (EMT) is a pivotal step involved in cancer recurrence and metastasis. In addition, the activation of the EMT program can induce a cancer stem cell (CSC)-like phenotype and programmed death-ligand 1 (PD-L1) expression in head and neck squamous cell carcinoma (HNSCC). The CMTM family has reported as an important regulator in this process. Here, we investigated the role of CMTM4 in HNSCC. We indicated that CMTM4 was overexpressed in human and mouse HNSCC samples and in HNSCC cell lines by immunohistochemistry and Western blot. A high expression level of CMTM4 was correlated with advanced lymph node metastasis and a negative prognosis. CMTM4-knockdown by small interfering RNA downregulated the EMT process and inhibited the migration and invasion abilities of tumor cells. Moreover, knockdown of CMTM4 decreased CSC-associated markers via the protein kinase B pathway. Notably, CMTM4-knockdown inhibited the expression of interferon-γ induced PD-L1 in HNSCC cells. A positive correlation was found between CMTM4 expression and CD8+ and PD-1+ cell density in the stroma. Our findings indicated that CMTM4 may play an important role in regulating EMT/CSC phenotypes and PD-L1 expression. This study may reinforce the interest in CMTM4 as a potential target for the prognosis and treatment of HNSCC.

Circular RNA circSMARCA5 is a prognostic biomarker in patients with malignant tumor: a meta-analysis

BackgroundMalignant tumor is one of the most serious diseases endangering human health. Circular RNAs play an important role in the tumorigenesis and progression of various malignant tumors. Although various studies have investigated the biological function of circular RNA circSMARCA5 in malignant tumors, the prognostic value of circSMARCA5 in malignant tumor patients has not been systematically analyzed.MethodsRelevant studies were obtained from the PubMed and Web of Science database. The quality of the enrolled studies was evaluated using the Newcastle-Ottawa Scale quality assessment system. Survival features and clinicopathological features were assessed using pooled hazard ratios and odds ratios with 95% confidence intervals, respectively.ResultsOverall, 7 relevant publications were enrolled in the meta-analysis. CircSMARCA5 expression was significantly correlated with better OS (HR = 0.51, 95%CI 0.41–0.65) or DFS/RFS/PFS (HR = 0.56, 95%CI 0.43–0.73) in malignant tumors. In the pooled analyses of clinicopathological characteristics, malignant tumors with higher circSMARCA5 were better differentiated (OR = 0.41, 95%CI 0.19–0.88). CircSMARCA5 expression was correlated with less advanced TNM stage (OR = 0.33, 95%CI 0.19–0.55). Moreover, malignant tumors with higher circSMARCA5 expression have less advanced lymph node metastasis (OR = 0.26, 95%CI 0.08–0.79).ConclusionThese results indicated that circSMARCA5 was a promising biomarker in malignant tumors, which may potentially facilitate clinical decisions in the future.

MiR-139 Modulates Cancer Stem Cell Function of Human Breast Cancer through Targeting CXCR4.

Simple SummaryThe C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various cancer stem/progenitor cells via activation of the epithelial-mesenchymal transition (EMT) program to facilitate tumor cell aggressiveness in the premetastatic niche. Through miRNAs microarray and bioinformatics analysis, we confirmed that miR-139 directly interacted with the 3′-untranslated region (3′-UTR) of CXCR4. Overexpression of miR-139 down-modulated CXCR4/p-Akt axis to attenuate invasion and migration of human breast cancer stem cells both in vitro and in vivo. Furthermore, miR-139 expression assessed by quantitative real-time PCR (qRT-PCR) in laser capture microdissected tumor samples significantly correlated with more advanced tumors in patients with breast cancer. Our findings provide support to account for the preferential role of miR-139 in interrupting breast cancer progression, identifying miR-139 as a potential biomarker in prediction of breast cancer invasiveness.Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3′-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-overexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.

The correlation between tumor-associated macrophage infiltration and progression in cervical carcinoma.

Tumor microenvironment (TME) plays a particularly important role in the progression, invasion and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the tumor microenvironment in CC. However, the results of studies on the correlation between TAMs and progression in CC are still controversial. This research aimed to investigate the relationship between TAMs infiltration and progression in CC. A total of 100 patients with CC were included in the study. The correlation between TAMs and clinicopathologic features was studied. Besides, a systematic literature search was conducted from legitimate electronic databases to specifically evaluate the role of TAMs in TME of cervical carcinoma. In the meta-analysis, high stromal CD68+ TAMs density was relevant to lymph node metastasis (WMD = 11.89, 95% CI: 5.30–18.47). At the same time, CD163+ M2 TAM density was associated with lymph node metastasis (OR = 2.42, 95% CI: 1.09–5.37; WMD = 39.37, 95% CI: 28.25–50.49) and FIGO stage (WMD = -33.60, 95% CI: -45.04 to -22.16). This was further confirmed in the experimental study of 100 tissues of cervical cancer. It supported a critical role of TAMs as a prospective predictor of cervical cancer. In conclusion, CD68+ TAM and CD163+ M2 TAM infiltration in CC were associated with tumor progression. And CD163+ M2 TAM infiltration was associated with more advanced FIGO stage and lymph node metastasis in CC.

Added Value of MRI for Invasive Breast Cancer including the Entire Axilla for Evaluation of High-Level or Advanced Axillary Lymph Node Metastasis in the Post–ACOSOG Z0011 Trial Era

Background In the post-American College of Surgeons Oncology Group Z0011 trial era, radiologists have increasingly focused on excluding high-level or advanced axillary lymph node metastasis (ALNM) by using an additional MRI scan positioned higher than lower axillae; however, the value of these additional scans remains undetermined. Purpose To evaluate whether a standard MRI protocol is sufficient to exclude high-level or advanced ALNM in breast cancer or additional MRI of entire axilla is needed. Materials and Methods This retrospective study evaluated women with invasive breast cancer who underwent breast MRI from April 2015 to December 2016. Some underwent neoadjuvant chemotherapy (NAC) and others underwent upfront surgery. Standard (routine axial scans including the lower axillae) and combined (routine axial scans plus additional scans including the entire axilla) MRI protocols were compared for high-level or advanced ALNM detection. Clinical-pathologic characteristics were analyzed. Uni- and multivariable logistic regression was performed to identify predictors of high-level or advanced ALNM. Results A total of 435 women (mean age ± standard deviation, 52 years ± 11) were evaluated (65 in the NAC group, 370 in the non-NAC group). With the standard MRI protocol, predictors of high-level ALNM were peritumoral edema (odds ratio [OR], 12.3; 95% CI: 3.9, 39.4; P < .001) and positive axilla (OR, 5.9; 95% CI: 2.0, 15.2; P < .001). Only three of 289 women with negative axillae without peritumoral edema had high-level ALNM. Predictors of advanced ALNM were positive axillae (OR, 8.9; 95% CI: 3.7, 21.5; P < .001) and peritumoral edema (OR, 2.8; 95% CI: 1.1, 6.9; P = .03). Only six of 310 women who had negative axillae without peritumoral edema had advanced ALNM. Conclusion The performance of standard MRI was satisfactory in excluding high-level and advanced axillary lymph node metastasis in most patients with breast cancer. However, the presence of peritumoral edema or positive axillae in the MRI findings emphasizes the benefits of a combined MRI protocol. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Abe in this issue.

Beclin-1 is a Promising Prognostic Biomarker in a Specific Esophageal Squamous Cell Carcinoma Population.

The effects of autophagy and apoptosis in the prognostic assessment and treatment of Esophageal squamous cell carcinoma (ESCC) remain to be elucidated. Here, we conducted a retrospective study on the histopathology of ESCC, investigated the expression of Beclin-1 and Bcl-2 proteins (both autophagy- and apoptosis-related) in esophageal cancer tissue, and analyzed the significance of these proteins for the prognosis of ESCC. In the present study, the expression level of Beclin-1 in ESCC was significantly lower than that in adjacent tissues (p < 0.01), whereas the expression level of Bcl-2 showed the opposite pattern (p < 0.01). Furthermore, low expression of Beclin-1 was associated with more advanced ESCC stages and lymph node metastasis. However, high expression of Bcl-2 was associated with more advanced ESCC stages, deeper tumor invasion, and lymph node metastasis. Moreover, the relationship between Bcl-2 expression and OS was not significant (p > 0.05), whereas Beclin-1 expression was significantly associated with OS (p < 0.05). Subgroup analysis showed that Beclin-1 expression was significantly associated with OS in the high-Bcl-2-expression group but not in the low-Bcl-2-expression group. Importantly, Beclin-1 upregulation or downregulation significantly upregulated or downregulated invasion, respectively, in EC9706 cells in combination with high expression but not low expression of Bcl-2. These findings reveal that differences in autophagy and apoptotic states and their activities may promote malignant tumor differentiation, which could lead to a more aggressive esophageal squamous cell phenotype and a worse survival prognosis. Here, Beclin-1 was shown to be a promising prognostic biomarker and therapeutic target for patients with ESCC in the high-Bcl-2-expression population.

Clinicopathological characteristics and prognostic factors of cervical adenocarcinoma

We aimed to assess the clinicopathological features and to determine the prognostic factors of cervical adenocarcinoma (AC). Relevant data were extracted from surveillance, epidemiology and end results database from 2004 to 2015. The log-rank test and Cox proportional hazard analysis were subsequently utilized to identify independent prognostic factors. A total of 3102 patients were identified. The enrolled patients were characterized by higher proportion of early FIGO stage (stage I: 65.9%; stage II: 14.1%), low pathological grade (grade I/II: 49.1%) and tumor size ≤ 4 cm (46.8%). The 5- and 10-year cancer-specific survival rates of these patients were 74.47% and 70.00%, respectively. Meanwhile, the 5- and 10-year overall survival (OS) rates were 71.52% and 65.17%, respectively. Multivariate analysis revealed that married status, surgery as well as chemotherapy were independent favorable prognostic indicators. Additionally, aged > 45, tumor grade III/IV, tumor size > 4 cm, advanced FIGO stage and pelvic lymph node metastasis (LNM) were unfavorable prognostic factors (all P < 0.01). Stratified analysis found that patients without surgery could significantly benefit from chemotherapy and radiotherapy. In addition, chemotherapy could significantly improve the survival in stage II–IV patients and radiotherapy could only improve the survival in stage III patients (all P < 0.01). Marital status, age, grade, tumor size, FIGO stage, surgery, pelvic LNM and chemotherapy were significantly associated with the prognosis of cervical AC.

Impact of resection margin status on survival in advanced N stage pancreatic cancer \u2013 a multi-institutional analysis

BackgroundThe present study aimed to examine the impact of microscopically tumour-infiltrated resection margins (R1) in pancreatic ductal adenocarcinoma (PDAC) patients with advanced lymphonodular metastasis (pN1–pN2) on overall survival (OS).MethodsThis retrospective, multi-institutional analysis included patients undergoing surgical resection for PDAC at three tertiary university centres between 2005 and 2018. Subcohorts of patients with lymph node status pN0–N2 were stratified according to the histopathological resection status using Kaplan-Meier survival analysis.ResultsThe OS of the entire cohort (n = 620) correlated inversely with the pN status (26 [pN0], 18 [pN1], 11.8 [pN2] months, P < 0.001) and R status (21.7 [R0], 12.5 [R1] months, P < 0.001). However, there was no statistically significant OS difference between R0 versus R1 in cases with advanced lymphonodular metastases: 19.6 months (95% CI: 17.4–20.9) versus 13.6 months (95% CI: 10.7–18.0) for pN1 stage and 13.7 months (95% CI: 10.7–18.9) versus 10.1 months (95% CI: 7.9–19.1) for pN2, respectively. Accordingly, N stage–dependent Cox regression analysis revealed that R status was a prognostic factor in pN0 cases only. Furthermore, there was no significant survival disadvantage for patients with R0 resection but circumferential resection margin invasion (≤ 1 mm; CRM+; 10.7 months) versus CRM-negative (13.7 months) cases in pN2 stages (P = 0.5).ConclusionsAn R1 resection is not associated with worse OS in pN2 cases. If there is evidence of advanced lymph node metastasis and a re-resection due to an R1 situation (e.g. at venous or arterial vessels) may substantially increase the perioperative risk, margin clearance in order to reach local control might be avoided with respect to the OS.

Evaluation of microRNAs as potential biomarkers in circulating HPV-DNA-positive non-small cell lung cancer patients

ABSTRACT The aim of the present study was to identify the potential risk of circulating-HPV-DNA in non-small cell lung cancer (NSCLC) and to analyze abnormally expressed miRNAs in circulating HPV-DNA-positive NSCLC. HPV universal primers were used to detect the presence of HPV-DNA in the peripheral blood of 100 patients with NSCLC. The relationship between circulating-HPV-DNA and NSCLC patients characteristics was analyzed. Then, eight differentially expressed miRNAs in NSCLC were screened based on the TCGA database. The levels of miRNAs in circulating HPV-DNA-positive NSCLC patients were detected by real-time quantitative PCR. ROC curves were generated to evaluate the diagnostic performance. Circulating-HPV-DNA was found in 16 patients. The proportion of HPV-DNA-positive patients with poorly differentiated NSCLC, advanced lung cancer and lymph node metastasis was higher than that of HPV-DNA-negative patients. The levels of miR-183, miR-210 and miR-182 were significantly higher and miR-144 was significantly lower in HPV-DNA-positive NSCLC than those in HPV-DNA-negative NSCLC patients. When using a single miRNA to identify circulating HPV-DNA-positive NSCLC patients, miR-210 had a higher area under the ROC curve (AUC) than other miRNAs, and its sensitivity and specificity were also higher. In addition, the combination of two miRNAs was more effective than a single miRNA. Among them, miR-210+ miR-144 had the highest AUC value and showed the best prediction performance. Circulating-HPV-DNA may serve as a risk factor in NSCLC. Plasma miR-183, miR-210, miR-182 and miR-144 can be used as reliable biomarkers to identify circulating HPV-DNA-positive NSCLC.

Human circular RNA hsa_circRNA_101705 (circTXNDC11) regulates renal cancer progression by regulating MAPK/ERK pathway

ABSTRACT Circular RNAs (circRNAs) play essential roles in the progression of human tumors, including renal cell carcinoma (RCC). The present study aimed to explore the functions and potential mechanisms of human circular RNA hsa_circRNA_101705 (circTXNDC11) in RCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure circTXNDC11 expression in RCC tissues and cell lines. RNase R and actinomycin D assays were conducted to analyze the characteristic of circTXNDC11. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, and transwell invasion assay were performed to assess cell proliferation and invasion abilities. Western blotting was applied to assess the levels of MEK and ERK proteins in RCC cells. Murine xenograft model assay was conducted to deduce the role of circTXNDC11 in vivo. The current data showed that circTXNDC11 was overexpressed in RCC tissues and cells. The overexpression of circTXNDC11 is linked to advanced TNM stage and lymph node metastasis of renal cancer. Knocking down circTXNDC11 suppressed cell proliferation and invasion in vitro and reduced tumor growth in vivo. Mechanistically, circTXNDC11 promoted RCC growth and invasion by activating the MAPK/ERK pathway. Thus, the current findings identified circTXNDC11 as a novel regulator of RCC tumorigenesis through the regulation of the MAPK/ERK pathway, offering a potential therapeutic target for RCC treatment.

The role of endoscopic tumor length in resected esophageal squamous cell carcinoma: a retrospective study.

BackgroundIn esophageal squamous cell carcinoma (ESCC), tumor status is assessed on the basis of latitudinal invasion. Endoscopic tumor length (ETL) may represent the longitudinal scope of the primary tumor, and whether it affects tumor stage or prognosis is not entirely clear. In this study, we evaluated the role of ETL in patients with resected ESCC.MethodsThe relationships of ETL with pathological parameters (pT status and pN status) and overall survival (OS) were analyzed using data from patients with resected ESCC who were treated at Fujian Cancer Hospital between January 1997 and December 2013. Odds ratios (ORs) and hazard ratios (HRs) were fitted with locally weighted scatterplot smoothing, and the structural breakpoints for ETL were determined using the Chow test.ResultsA total of 721 patients with resected ESCC were enrolled. As the ETL increased in these patients, a rise in the risk of advanced pT status, nodal metastasis, and mortality was observed. Cutpoint analysis showed a breakpoint of 7.0 cm. A negative impact of ETL ≥7.0 cm was also found (adjusted HR, 1.335; 95% CI, 1.004–1.774). Seven independent prognostic factors, including sex, age, number of nodes dissected, T stage, N stage, tumor location, and ETL, were identified and entered into the nomogram. The calibration curves for 1-, 3-, and 5-year OS showed optimal agreement between nomogram prediction and actual observation (c-index: 0.688).ConclusionsLonger tumor length, with ETL ≥7.0 cm as the breakpoint, is a negative prognostic factor in patients with ESCC.

Surgery following neoadjuvant chemoradiation therapy in clinical N3 esophageal cancer results in improved survival: a propensity-matched analysis.

Esophageal cancer patients with extensive nodal metastases have poor survival, and benefit of surgery in this population is unclear. The aim of this study is to determine if surgery after neoadjuvant chemoradiotherapy (nCRT) improves overall survival (OS) in patients with clinical N3 (cN3) esophageal cancer relative to chemoradiation therapy (CRT) alone. The National Cancer Database was queried for all patients with cN3 esophageal cancer between 2010 and 2016. Patients who met inclusion criteria (received multiagent chemotherapy and radiation dose ≥30 Gy) were divided into two cohorts: CRT alone and nCRT + surgery. 769 patients met inclusion criteria, including 560 patients who received CRT alone, and 209 patients who received nCRT + surgery. The overall 5-year survival was significantly lower in the CRT alone group compared to the nCRT + surgery group (11.8% vs 18.0%, P < 0.001). A 1:1 propensity matched cohort of CRT alone and nCRT + surgery patients also demonstrated improved survival associated with surgery (13.11 mo vs 23.1 mo, P < 0.001). Predictors of survival were analyzed in the surgery cohort, and demonstrated that lymphovascular invasion was associated with worse survival (HR 2.07, P = 0.004). Despite poor outcomes of patients with advanced nodal metastases, nCRT + surgery is associated with improved OS. Of those with cN3 disease, only 27% underwent esophagectomy. Given the improved OS, patients with advanced nodal disease should be considered for surgery. Further investigation is warranted to determine which patients with cN3 disease would benefit most from esophagectomy, as 5-year survival remains low (18.0%).

LncRNA MAGI2-AS3 inhibits bladder cancer progression by targeting the miR-31-5p/TNS1 axis.

In this study, we performed bioinformatics analysis to identify the competing endogenous RNAs (ceRNAs) that regulate bladder cancer (BCa) progression. RNA-sequencing data analysis identified 2451 differentially expressed mRNAs, 174 differentially expressed lncRNAs, and 186 microRNAs (miRNAs) in BCa tissues (n=414) compared to the normal urothelial tissues (n=19) from the TGCA database. CeRNA network analysis of the differentially expressed lncRNAs and mRNAs showed strong positive correlation between lncRNA MAGI2-AS3 and Tensin 1 (TNS1) mRNA in BCa tissues. Bioinformatics analysis also showed that both MAGI2-AS3 and TNS1 mRNA sequences contain miR-31-5p binding sites. Furthermore, we observed significantly lower MAGI2-AS3 and TNS1 mRNA expression and higher miR-31-5p expression in the BCa tissues and cell lines (T24 and J82) compared with their corresponding controls. Functional and biochemical experiments in BCa cell lines including luciferase reporter assays showed that MAGI2-AS3 upregulated TNS1 by sponging miR-31-5p. Transwell assays showed that the MAGI2-AS3/miR-31-5p/TNS1 axis regulated migration and invasion ability of BCa cell lines. Moreover, immunohistochemical staining of paired BCa and normal urothelial tissues showed that low expression of TNS1 correlated with advanced tumor (T) stages and lymph node metastasis in BCa. In conclusion, our study demonstrates that the MAGI2-AS3/miR-31-5p/TNS1 axis regulates BCa progression.

High expression of CIN85 promotes proliferation and invasion of human esophageal squamous cell carcinoma.

SH3 domain-containing kinase-binding protein 1 (CIN85), an 85 kDa protein known to be a member of the signal adaptor family, is abnormally expressed in several human malignancies and has been found to be involved in the growth, migration and invasion of these tumors. The objective of the present study was to clarify the clinical significance of CIN85 in human esophageal squamous cell carcinoma (ESCC), as well as its in vitro functions. CIN85 expression was evaluated in 129 cases of ESCC and its adjacent normal tissues using immunohistochemistry to explore its clinical relevance and prognostic value. The functions of CIN85 in the ESCC TE1 cell line were analyzed in vitro using the interfering short hairpin RNA silencing technique. MTS, wound healing, clone formation and Transwell assays were used to detect the proliferation, migration and invasion of ESCC cells. CIN85 expression was identified mainly in ESCCs and their adjacent normal tissues, and the high expression of CIN85 was significantly associated with advanced Tumor Node Metastasis stage and lymph node metastasis. CIN85 gene silencing significantly inhibited TE1 cell proliferation, migration and invasion. These results demonstrated that CIN85 was highly expressed in advanced stage ESCC and lymph node metastasis, and played a critical role in tumor proliferation and progression. Therefore, CIN85 may be a promising therapeutic target for human ESCC.