Advanced Tumor Size Research Articles

Exosome-mediated miR-9-5p promotes proliferation and migration of renal cancer cells both in vitro and in vivo by targeting SOCS4

Exosomes secreted by cancer cells play important roles in tumor progression by interacting with cell receptors. Renal cancer derived exosomes contain miRNAs which are associated with cell proliferation and invasion. Micro RNA 9–5 (miR-9-5) is highly expressed in the serum of renal cancer patients with advanced (tumor size - node - metastasis) TNM stage and Fuhrman grade. miR-9-5p is extensively expressed in exosomes derived from renal cancer cells. Overexpression of miR-9-5p promotes proliferation and invasion of A-704 (a cancer cell line of human kidney) cells via targeting and deregulating SOCS4 mRNA. Inhibition of the Janus kinase (JAK)/signaling transducer and activator of transcription (STAT) pathway by SOCS4 will be reduced, which leads to phosphorylation of STAT3 and JAK. Activated cytokine signaling promotes cell proliferation and invasion, and inhibits apoptosis. Moreover, overexpression of SOCS4 reduces miR-9-5p levels and plays an opposite role in cell. To conclude, exosomal miR-9-5p plays important roles in renal cancer both in vivo and in vitro, indicating it may be used as biomarker for diagnosis and for monitoring the efficacy if therapy.

LncRNA LINC00689 Promotes the Progression of Gastric Cancer Through Upregulation of ADAM9 by Sponging miR-526b-3p.

IntroductionIncreasing studies have demonstrated that noncoding RNAs, including miRNAs and lncRNAs, have vital roles in mediating cancer progression. However, the expression features and biological functions of LINC00689 in gastric cancer (GC) remain largely unknown. This study was designed to investigate the functions of LINC00689, miR-526b-3p and ADAM9 as well as their interactions in GC.MethodsReal time PCR(RT-PCR) was used to detect the expression of LINC0068, miR-526b-3p and ADAM9 in both GC tissues or cell lines. Gain- and loss- of functions of assays were conducted to verify the role of LINC0068, miR-526b-3p and ADAM9 in GC development. Cell proliferation were determined by CCK8 assay and transwell assay and scratch wound-healing assay were used to test cell invasion and migration. Further, the relationships between LINC00689 and miR-526b-3p, miR-526b-3p and ADAM9 were predicted by bioinformatics analysis and then proved by Luciferase reporter assay and RNA Immunoprecipitation(RIP) assay.ResultsWe found that LINC00689 was upregulated in GC tissues and positively correlated with advanced tumor stage and tumor size, while miR-526b-3p was downregulated. Furthermore, gain- and loss-of-function experiments revealed that LINC00689 promoted the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of GC cells, while miR-526b-3p had the opposite effects. The underlying mechanisms indicated that LINC00689 functioned as a competing endogenous RNA (ceRNA) by sponging miR-526b-3p in GC cells. Further investigations confirmed that ADAM9 was a direct target of miR-526b-3p and positively modulated the progression of GC.ConclusionOur study suggests that LINC00689 functions as a novel oncogenic lncRNA in the development of GC by promoting ADAM9 expression through suppression of miR-526b-3p.

Circular RNA hsa_circ_0002052 promotes osteosarcoma via modulating miR-382/STX6 axis.

Circular RNAs (circRNAs) exert pivotal effects on regulating the progression of osteosarcoma (OS). It was found through microarray analysis that circ-0002052 is abnormally expressed in OS, but the role of circ-0002052 in OS remains obscure. The results of this research manifested that relative to that in non-tumor controls, circ-0002052 level was raised in OS tissues. Up-regulated circ-0002052 was associated with advanced stage, tumor size, and metastasis. Additionally, circ-0002052 elevation indicated a low survival rate in OS patients and silencing of circ-0002052 suppressed proliferation, migration, and invasion of OS cells. It was proved that circ-0002052 sponged miR-382 and stimulated STX6 expression, thus activating Wnt/β-catenin. The function of circ-0002052 reduction in OS cells was effectively reversed by miR-382 suppression. To sum up, it can be concluded that circ-0002052, functioning as a sponge for miR-382, enhances the activation of Wnt/β-catenin mediated by STX6 to stimulate the progression of OS, and circ-0002052 may be an underlying treatment target and a biomarker for prognosis of osteosarcoma.

Glucose Transporter-1 (GLUT-1) Expression is Associated with Tumor Size and Poor Prognosis in Locally Advanced Gastric Cancer.

BackgroundThe clinicopathological parameters associated with glucose transporter-1 (GLUT-1) expression in advanced gastric cancer are still controversial. This study aimed to determine the clinicopathological parameters and prognosis associated with GLUT-1 expression in advanced gastric cancer.Material/MethodsThe GLUT-1 expression level of 234 consecutive gastric cancer samples was detected by immunohistochemical staining and evaluated by semiquantitative analysis. The clinicopathological data and expression level of GLUT-1 of enrolled patients were retrospectively analyzed with univariate and multivariate analyses.ResultsTumor size, depth of invasion, and Lauren classification were independent factors related to GLUT-1 expression (P<0.05). Within advanced gastric cancer, tumor size and Lauren type were independent factors associated with GLUT-1 (P=0.011, P<0.001, respectively). The mean survival time of GLUT-1-positive patients with stage M0 advanced gastric cancer who had undergone radical gastrectomy was shorter than that of GLUT-1-negative patients (61.26±6.12 versus 80.88±7.38, P=0.044). GLUT-1 was an independent prognosis factor in locally advanced gastric cancer patients who had undergone radical gastrectomy (hazard ratio [HR] 1.769, P=0.046). The mean survival time of adjuvant chemotherapy was significantly better than no adjuvant chemotherapy in the GLUT-1-positive group (71.10±6.88 versus 24.65±8.69, P<0.001) and in the GLUT-1 negative group (87.48±7.99 versus 49.39±11.71, P<0.001).ConclusionsTumor size and Lauren type independently affected GLUT-1 expression in advanced gastric cancer. GLUT-1 was not only related to poor prognosis but also predicted to be a metabolic biomarker for intestinal type in locally advanced gastric cancer. The relationship among GLUT-1, hepatic metastasis and chemotherapy regimens, and mechanism of chemotherapy responses related to GLUT-1 should be further investigated.

Altered expression of 17‑β‑hydroxysteroid dehydrogenase type2 and its prognostic significance in non‑small cell lung cancer.

Numerous studies have reported that oestrogens may contribute to the development of non small cell lung cancer (NSCLC). Although different steroidogenic enzymes have been detected in the lung, the precise mechanism leading to an exaggerated accumulation of active oestrogens in NSCLC remains unexplained. 17 β Hydroxysteroid dehydro genase type 2 (HSD17B2) is an enzyme involved in oestrogen and androgen inactivation by converting 17 β oestradiol into oestrone, and testosterone into 4 androstenedione. Therefore, the enzyme serves an important role in regulation of the intra cellular availability of active sex steroids. This study aimed to determine the expression levels of HSD17B2 in lung cancer (LC) and adjacent histopathologically unchanged tissues obtained from 161 patients with NSCLC, and to analyse the association of HSD17B2 with clinicopathological features. For that purpose, reverse transcription quantitative PCR, western blotting and immunohistochemistry were conducted. The results revealed that the mRNA and protein expression levels of HSD17B2 were significantly decreased in LC tissues compared with matched controls (P<10 6). Conversely, strong cytoplasmic staining of HSD17B2 was detected in the unchanged respiratory epithelium and in glandular cells. Notably, a strong association was detected between reduced HSD17B2 expression and advanced tumour stage, grade and size. Furthermore, it was revealed that HSD17B2 may have potential prognostic significance in NSCLC. A log-rank test revealed the benefit of high HSD17B2 protein expression for the overall survival (OS) of patients (P=0.0017), and multivariate analysis confirmed this finding (hazard ratio=0.21; 95% confidence interval=0.07-0.63; P=0.0043). Stratified analysis in the Kaplan Meier Plotter database indicated that patients with higher HSD17B2 expression presented better OS and post-progression survival. This beneficial effect was particularly evident in patients with adenocarcinoma and during the early stages of NSCLC. Decreased expression of HSD17B2 appears to be a frequent feature in NSCLC. Retrospective analysis suggests that the HSD17B2 mRNA and protein status might be independent prognostic factors in NSCLC and should be further investigated.

Role of overexpression of myeloid cell leukemia-1-long in prognosis of malignant pleomorphic adenoma

Objective: To evaluate the clinicopathological significance of the expression of the two myeloid cell leukemia-1 isoforms, myeloid cell leukemia-1-long (Mcl-1L) and myeloid cell leukemia-1-short (Mcl-1S) in malignant pleomorphic adenoma (MPA). Methods: A total of 56 patients with MPA treated with surgery, the expression of Mcl-1L and Mcl-1S were detected by quantitative real-time PCR (qPCR) in mRNA level, and by Western blotting in protein level, respectively. The correlation between clinicopathological parameters (gender, age, site, habits, size, node, metastasis, recurrence) was done using the chi-square test. Kaplan-Merier curve was used to analyze the survival in all patients, Log Rank test was performed to observe the difference between groups. Cox's proportional hazard test was used to identify the factors that were independent predictors of survival. Results: qPCR showed overexpression of Mcl-1L in 66.1%MPA patients (37/56), with significant difference in terms of tumor site, significantly higher expression of Mcl-1L in MPA (parotid gland: 2.21±1.07, sublingual gland: 2.12±1.08, other sites: 1.83±0.81) than benign pleomorphic adenoma tissue (1.00±0.19) (P<0.01). Western blotting analysis showed significantly higher expression of Mcl-1L in MPA (parotid gland: 1.02±0.43, sublingual gland: 0.71±0.29, other sites: 0.70±0.30) than benign pleomorphic adenoma tissue (0.39±0.08) (P<0.01). In malignant pleomorphic adenoma patients, high Mcl-1L expression was significantly associated with node positivity (P=0.045), advanced tumor size (P=0.002). Kaplan-Meier survival line analysis indicated a significantly lower survival time in Mcl-1L higher-expression patients (24.79±9.71) than lower-expression patients (30.59±9.01) (P=0.017). Multivariate analysis indicated Mcl-1L to be an independent prognostic factor for MPA (P=0.002). Conclusions: The studies suggest that overexpression of Mcl-1L is associated with poor prognosis in MPA. Mcl-1L is an independent prognostic factor in malignant pleomorphic adenoma.

The long non-coding RNA HOXA11-AS promotes epithelial mesenchymal transition by sponging miR-149-3p in Colorectal Cancer.

Background: Metastasis is the primary cause of death in colorectal cancer (CRC); the underlying mechanisms remain partly unknown. In this study, we aim to investigate the value of HOXA11-AS in survival evaluation and the potential role of HOXA11-AS/miR-149-3p axis in the CRC metastasis.Methods: The expressions of HOXA11-AS, both in obtained CRC samples and adjacent noncancerous tissues, were analyzed in survival evaluation. Competing endogenous RNAs (CeRNAs) Analysis were employed to reveal the potential relationship between HOXA11-AS and miR-149-3p. It was further confirmed by Quantitative real-time polymerase chain reaction (qRT-PCR) and Dual-luciferase reporter assay. Migration and invasion assay were used to verify the potential role of HOXA11-AS and miR-149-3p in the regulation of CRC metastasis. The potential pathway was explored by Western blot analysis.Results: The expression of HOXA11-AS in the CRC tissue is significantly higher than the expression in adjacent noncancerous tissue (p<0.0001). High expressions of HOXA11-AS were noticeably correlated with clinicopathologic characteristics including advanced clinical stage (p=0.021), larger tumor size (p<0.001) and frequent tumor recurrence (p=0.001). The overall survival in HOXA11-AS-High group was significantly shorter than the HOXA11-AS-Low group (p<0.001). Advanced clinical stage, tumor size and high expression of HOXA11-AS were showed as independent prognostic prediction factors for the 5-year tumor relapse of CRC patients (p<0.001). HOXA11-AS acts as a potential molecular sponge for miR-149-3p, in the promotion of CRC metastasis. In the miR-149-3p mimic-treated group, the expression of E-cadherin was increased, whereas the expression of N-cadherin, Snail, Slug, TGF-β1, Wnt2b, Twist and C/EBPβ was decreased.Conclusion: This study demonstrates that high expression of HOXA11-AS is correlated with CRC progression and poor prognosis and may promote metastasis via EMT by modulating miR-149-3p.

Analysis of the surgical management of patients with recurrent cervical cancer after radiotherapy and chemotherapy.

To analyze the results of morbidity and survival after curative and palliative surgery in recurrent cervical cancer patients who underwent chemoradiation as their primary treatment. Another goal was to assess the factors associated with curative and non-curative procedures. This was a retrospective cohort consisting of patients undergoing surgery curative and palliative from January 2011 to December 2017 at a high complexity oncology center. Outcome of morbidity was reported according to the Clavien-Dindo classification, and survival analysis was carried out using the Kaplan-Meir method. To assess the factors associated with the procedures, a univariate analysis using the Mann-Whitney U test was performed. Two radical hysterectomies, three pelvic exenterations with curative intent, and five palliatives pelvic exenterations were performed. In the curative group, there were major complications in 40% of the cases, and the median survival time was 16 months. In the palliative group, there were major complications in 60% of the cases, and the median survival time was 5 months. Advanced staging (p-value= 0.02), symptoms (p-value=0.04), tumor size greater than five centimeters (p-value=0.04), and more than three organs involved (p-value=0.003) were factors significantly associated with non-curative surgery. The morbidity rates of this study were higher in palliative group, and the median survival time was lower in the palliative group than the curative group, but this difference in survival was not statistically significant. Advanced stage, symptoms, tumor size and number of organs involved are factors that should be taken into consideration when indicating surgical salvage.

MiR-216b-5p inhibits cell proliferation in human breast cancer by down-regulating HDAC8 expression

AimOver-expression of histone deacetylase 8 (HDAC8) has been demonstrated in breast cancer. But the underlying molecular mechanism of HDAC8 on the progression of breast cancer remains unknown. MicroRNAs (miRs) are proposed as important molecules in cancer progression by targeting specific oncogenes or tumor-suppressor genes. Our overall objective was to assess the miR-216b-5p role on HDAC8; and its impacts on breast cancer (BC) progression. Main methodsWe acquired cancerous and noncancerous tissues from Iran Tumor Bank (I.T.B). The MDA-MB-231, MCF-7 and MCF-10A BC cell lines were also purchased. The tissue and cell line expression levels of miR-216b-5p and HDAC8 were determined by quantitative real-time PCR (qPCR). We next measured protein levels of HDAC8 by Western blotting assay. The cell cycle, cell proliferation, and colony formation assay were determined. Finally, we investigated the role of HDAC8 using a knockout vector; and confirmed the targeting of 3′ untranslated region (3′-UTR) of HDAC8 through miR-216b-5p using a luciferase reporter assay. Key findingsOur results demonstrated a significant decrease in miR-216b-5p, and remarkable increase in HDAC8 levels within human breast cancer tissues and cell lines. The lower levels of miR-216b-5p were negatively correlated with lymph node metastasis and advanced tumor size. The overexpression of miR-216b-5p in BC cell lines inhibited cellular proliferation and progression. HDAC8 was directly down-regulated by miR-216b-5p and knockout of HDAC8 showed the similar effects as miR-216b-5p overexpression. SignificanceBriefly, HDAC8 is an oncogene that accelerate breast cancer proliferation and progression and miR-216b-5p modulates those functions by binding to HDAC8 3′-UTR.

The Long Noncoding RNA LINC00908 Facilitates Hepatocellular Carcinoma Progression Via Interaction With Sox-4.

BackgroundThe hepatocellular carcinoma (HCC) is a highly aggressive and common malignancy worldwide. Accumulating evidence has demonstrated a pivotal role of long noncoding RNAs (lncRNAs) in various tumors. However, the function of intergenic lncRNA LINC00908 is still unknown in HCC.MethodsThe RT-qPCR method was used to quantify the expression of LINC00908. Migration and viability assay were performed to evaluate the in vitro effect and xenograft tumor model was used to measure the in vivo effect. Immunoblot was used to identify the association of LINC00908 with Sox-4 and the stability of Sox-4.ResultsWe found a novel lncRNA related to HCC. LINC00908 is highly expressed in tumorous tissues and cell lines compared with normal ones. High LINC00908 expression correlated with advanced TNM stages, tumor size and metastasis. LINC00908 promoted the migration and viability of HCC cells. The in vivo xenograft tumor growth and proliferation were also enhanced by LINC00908 overexpression and inhibited by LINC00908 silence. LINC00908 physically interacted with Sox-4, and the association between LINC00908 and Sox-4 increased the stability of Sox-4 by reducing proteasomal degradation.ConclusionTaken together, our current work has identified a novel lncRNA LINC00908 which is critically involved in HCC progression. The LINC00908-Sox-4 axis might provide a new and potential target for pharmaceutical therapies.

Outcomes of Women with Non-Metastatic Triple-Negative Breast Cancer in Oman: A single-centre experience.

ObjectivesTriple-negative breast cancer (TNBC) is one of the most aggressive and heterogeneous variants of breast cancer. However, little is known regarding the prevalence and outcome of this entity in the Middle East. This study aimed to evaluate the outcomes of TNBC patients at a university hospital in Oman.MethodsThis retrospective study took place at the Sultan Qaboos University Hospital, Muscat, Oman, in May 2017. All patients diagnosed with non-metastatic TNBC between December 2000 and December 2015 were included. The patients’ electronic medical records were reviewed to identify their clinical and pathological characteristics as well as survival outcomes.ResultsA total of 79 patients were diagnosed with non-metastatic TNBC during the study period. The median age was 46 years, with approximately one-third of patients (31.6%) under 40 years of age. Almost half had an advanced tumour size (49.4%) or node-positive disease (48.1%) at presentation and only 16.6% demonstrated a complete pathological response (pCR) to neoadjuvant chemotherapy. The median survival for all patients was not reached within the study period; however, the median overall survival for stage III patients was 44.6 months. The five-year overall survival for all patients was 64%, increasing to 100% and 72% for patients with stage I and II, respectively, and dropping to 47% for those with stage III disease.ConclusionThe findings of this study indicate that the majority of women with TNBC in Oman present at an advanced stage; moreover, such women have low rates of pCR to neoadjuvant chemotherapy and poor five-year survival.

Sinonasal mucoepidermoid carcinoma: a review of the National Cancer Database

Primary sinonasal mucoepidermoid carcinoma (SN-MEC) is a malignancy arising from seromucinous glands of the nasal cavity and paranasal sinuses. Given its rarity, few large-scale studies have been performed. In this study we describe the incidence and determinants of survival of patients with SN-MEC leveraging the National Cancer Database (NCDB). This was a retrospective, population-based cohort study of patients diagnosed with SN-MEC between 2004 and 2012 within the NCDB. The main outcome measure was overall survival (OS). A total of 164 patients were identified. The cohort was composed of 47.6% males. Mean age at diagnosis was 59.7 years. The maxillary sinus was the most common primary site, accounting for 45.7% of cases. Eleven percent of patients presented with nodal disease, whereas 2.1% had distant metastases. Stage IV disease was seen in 30.4% of cases. A total of 79.8% of the patients underwent surgery, 61.0% received radiation therapy, and 15.1% had chemotherapy. OS at 1, 2, and 5 years was 83%, 77.0%, and 57%, respectively. On multivariate analysis, Medicaid insurance status (hazard ratio [HR], 7.29; 95% confidence interval [CI], 1.74-30.57), advanced tumor size (HR, 4.94; 95% CI, 1.19-20.5), and advanced nodal disease (N1: HR, 9.48; 95% CI, 1.66-54.23; N2B: HR, 19.3; 95% CI, 1.07-350.64) were associated with worse OS. Mucoepidermoid carcinoma is the most common salivary gland malignancy but a rare sinonasal malignancy, with 5-year survival for SN-MEC approximating 50%. A significant proportion of patients present with advanced disease. Both socioeconomic factors and tumor characteristics are associated with survival.

Axl and autophagy LC3 expression in tumors is strongly associated with clinical prognosis of hepatocellular carcinoma patients after curative resection.

BackgroundThe role of Axl and LC3 as predictors of tumor recurrence and overall survival (OS) after hepatocellular carcinoma (HCC) resection remains unclear.MethodsWe retrospectively included 535 HCC patients who underwent hepatectomy from 2010 to 2014 in this study. Axl and the autophagy‐related marker LC3 were immunohistochemically assessed in tumors.ResultsAxl expression was significantly associated with advanced clinicopathological features, including cirrhosis, microvascular invasion, macrovascular invasion, tumor size, BCLC stage, recurrence, and mortality. HCC recurrence occurred in 245 patients, and 219 patients died. The 5‐year cumulative incidences of HCC recurrence and OS rate after HCC resection were 53.3% and 58.8%, respectively. In the Cox proportional analyses, high Axl expression and high LC3 expression were significantly associated with HCC recurrence (hazard ratio [HR]: 3.85, 95% confidence interval [CI]: 2.95‐5.02, P < 0.001; and HR: 0.38, 95% CI: 0.26‐0.55, P < 0.001, respectively). In addition, HCC recurrence (HR: 2.87, 95% CI: 2.01‐4.01, P < 0.0001), microvascular invasion (HR: 1.85, 95% CI: 1.08‐3.19, P = 0.026), hepatitis B virus‐related HCC (HR: 1.77, 95% CI: 1. 21‐2.56, P = 0.003), high Axl expression (HR: 1.66, 95% CI: 1.41‐1.97, P < 0.0001), antiviral therapy (HR: 0.54, CI: 0.38‐0.76, P < 0.001) and LC3 expression (HR: 0.41, 95% CI: 0.28‐0.58, P < 0.001) were significantly associated with mortality. Furthermore, patients with a combination of high Axl and low LC3 expression had the highest risk of HCC recurrence (HR: 6.53, 95% CI: 4.11‐10.4, P < 0.001) and mortality (HR: 6.66, 95% CI: 4.07‐10.9, P < 0.001). In patients with high Axl, low LC3, and combined high Axl and low LC3 expression, the 5‐year cumulative incidences of HCC recurrence and OS rate were 77.9%, 73.3%, and 90.0% and 28.8%, 26.7%, and 16.8%, respectively.ConclusionHigh Axl expression in tumors is associated with aggressive tumor behavior and worse clinical outcomes. Furthermore, the combination of high Axl and low LC3 expression significantly predicts poorer prognosis for HCC patients who underwent hepatectomy.

LncRNA AWPPH promotes osteosarcoma progression via activation of Wnt/β-catenin pathway through modulating miR-93-3p/FZD7 axis

Long noncoding RNAs (lncRNAs) have important regulatory roles in osteosarcoma (OS) progression. Recent researches have shown lncRNA AWPPH promotes lung cancer progression and bladder cancer development. Yet, the function of AWPPH in OS is unknown. In this research, results indicated AWPPH levels were increased in OS tissues in contrast to paracancerous controls. Up-regulated AWPPH was associated with advanced stage, tumor size and metastasis. Besides, AWPPH up-regulation indicated a low survival rate in OS patients. Silencing of AWPPH suppressed proliferation, migration and invasion of OS cells. Mechanistically, AWPPH was demonstrated to sponge miR-93-3p and promote FZD7 expression, causing activation of Wnt/β-catenin. Inhibition of miR-93-3p effectively reversed the effects of AWPPH knockdown on OS cells. Collectively, our findings suggested AWPPH may be a prognostic biomarker and potential therapeutic target. AWPPH enhances FZD7-mediated activation of Wnt/β-catenin by sponging miR-93-3p to promote OS progression.

Significance of PD-L1 clones and C-MET expression in hepatocellular carcinoma.

Programmed cell death ligand 1 (PD-L1) is an essential immune checkpoint protein implicated in immune evasion by malignant tumors. Overexpression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 is associated with poor prognosis in various types of cancer. Recently, multiple advances have occurred in the area of cancer immunotherapy. Inhibiting the ligation of PD-1 by PD-L1 has been the major focus of anti-tumor immunotherapy. In diagnostic pathology, it has become crucial to detect PD-L1+ tumor cases using a validated immunohistochemistry (IHC) approach. Preliminary data demonstrate that C-MET promotes survival of some (e.g., renal) cancer types through regulation of PD-L1. However, C-MET expression, and its association with PD-L1, has not been well-characterized in the context of hepatocellular carcinoma (HCC), and no anti-HCC immunotherapy is currently available in Korea. Therefore, it is crucial to investigate the expression of C-MET and PD-L1, and their association with clinicopathologic factors, to facilitate the development of targeted treatments for HCC. PD-L1 expression was examined in tumor cells (TC) and immune cells (IC) of 70 patient-derived HCC specimens using IHC. Two anti-PD-L1 monoclonal antibodies (MAbs), SP263 and SP142, were utilized. Additionally, TC C-MET expression was assessed. Correlations between PD-L1 expression (as identified by both MAbs), C-MET expression and clinicopathologic factors were assessed. More PD-L1+ cases were identified via SP263 than via SP142 when assessing both TC and IC; in the former group, SP236 identified 14/70 positive cases, while SP142 identified only 2/70. In the latter group, SP236 identified 49/70 positive cases, while SP142 identified 30/70. Both MAbs demonstrated a higher frequency of PD-L1 expression by IC than TC. The Edmondson-Steiner grade statistically correlated with a higher frequency of SP236-detected TC PD-L1 expression. C-MET was significantly associated with advanced tumor size and was positively correlated with SP263-detected PD-L1 expression in TC. These results suggest that C-MET may serve a role in regulating PD-L1 expression in HCC. Furthermore, while SP263 generally exhibited a higher sensitivity for PD-L1 detection, concordance in PD-L1+ case detection between the two different MAbs was generally good. These background data may be helpful in the development of targeted anti-HCC immunotherapy focused on PD-L1 or C-MET, and in evaluating selection criteria for target populations best suited to such treatments.

CCEPR is a novel clinical biomarker for prognosis and regulates cell proliferation through PCNA in osteosarcoma.

CCEPR (cervical carcinoma expressed PCNA regulatory lncRNA) has been found to be upregulated and enhance cell proliferation in human cancers. However, the role of CCEPR in osteosarcoma remains to be discovered. In this study, we found CCEPR expression was elevated in osteosarcoma tissue specimens and cell lines compared with adjacent normal tissue specimens and osteoblast cell line, respectively. Meanwhile, osteosarcoma patients with advanced stage or tumor size greater than 8 cm had higher expression of CCEPR than patients with early stage or tumor size less than or equal to 8 cm, respectively. Survival analysis suggested that osteosarcoma patients with high CCEPR expression had a worse overall survival rate than those with low CCEPR expression. The in vitro study indicated that CCEPR positively regulated proliferating cell nuclear antigen (PCNA) expression in osteosarcoma cells and silencing of CCEPR inhibited osteosarcoma cell proliferation through decreasing PCNA expression. In conclusion, CCEPR is a potential prognostic predictor and functions as oncogenic long non-coding RNA (lncRNA) to regulate cell proliferation via PCNA in osteosarcoma.

Performance of a Multidisciplinary Pancreatic Cancer Conference in Predicting and Managing Resectable Pancreatic Cancer.

Surgery is the curative treatment for pancreatic ductal adenocarcinoma (PDA). Guidelines recommend utilizing a multidisciplinary pancreatic cancer conference (MDPC) in treatment; however, data are limited. The objective of this study was to assess the accuracy of an MDPC. Patients with PDA presented at an MDPC were prospectively collected from April 2013 to August 2016. Patients were included if the MDPC predicted them to have resectable PDA and underwent upfront surgery. Secondary aims were to compare differences in tumor characteristics, time to surgery, and resection rates with patients prior to MDPC implementation (pre-MDPC). A total of 278 patients were presented at the MDPC. After excluding borderline and nonresectable cases, 91 patients were predicted as resectable on evaluation, and 70 were fit for surgery. The MDPC predicted resection in 91.4%. The MDPC had larger tumor size (32.6 vs 24.0 mm), greater proportion of stage II tumor, and a shorter time from diagnosis to resection (27.3 vs 35.5 days) compared with the pre-MDPC. Microscopically negative resections were similar between MDPC and pre-MDPC (85.9% vs 88.0%) despite advanced tumor size and stage. The MDPC demonstrates a high resection rate. Compared with a pre-MDPC, MDPC provides shorter time to surgery and selects for advanced tumors.

TP53 inactivation and expression of methylation-associated proteins in gastric adenocarcinoma with enteroblastic differentiation.

Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of aggressive adenocarcinoma. We demonstrated previously that GAED is genetically characterized by frequent TP53 mutation. In this study, we aimed to further clarify the mechanism of inactivation of TP53 in GAED in the light of promoter methylation of TP53, and expression of methylation-associated proteins such as Ten-eleven translocation (TET) 1 and 5-hydroxymethylcytosine (5-hmc) in addition to ATM mutations. We analyzed 51 cases of GAED. The ATM mutation was detected in only one case. Promoter methylation of TP53 was detected in 18% and frequency of loss of heterozygosity (LOH) at TP53 locus was 37.2%. Reduced TET1 expression was found in 29 cases (56.9%) and was significantly associated with advanced stage (p = 0.01), lymph node metastasis (p = 0.04), and macroscopic type (p = 0.01). Reduced 5-hmc expression was found in 28 cases (54.9%) and was significantly associated with advanced stage (p = 0.01), gender (p = 0.01), tumor location (p = 0.03), tumor size (p = 0.01), and lymph node metastasis (p = 0.01). Among 9 cases with TP53 promoter methylation, reduced expression of TET1 was observed in 6 cases, and reduced expression of 5-hmc was observed in 5 cases. Reduced expression of both TET1 and 5-hmc was significantly associated with adverse clinical outcomes. In summary, promoter methylation of TP53 is partly involved in loss of p53 expression. Aberrant methylation by reduced TET1 and 5-hmc may be involved in the development of aggressive GAED.

Cyclooxygenase-2 Expression and Its Correlation with Primary Tumor Size and Lymph Node Involvement in Nasopharyngeal Carcinoma.

AIM:This study aimed to observe the cyclooxygenase-2 expression and its correlation with tumour size and lymph node involvement in nasopharyngeal carcinoma.METHODS:This study was cross-sectional, that enrolled 126 samples diagnosed with nasopharyngeal carcinoma in Haji Adam Malik General Hospital, Medan, Indonesia which fulfilled the inclusion criteria.RESULTS:Based on this study, we found that the age peak incidence of nasopharyngeal carcinoma patients about a 41-60-year-old group (57.1%), dominated by men (71.4%). Through histopathological examination, non-keratinizing squamous cell carcinoma is the most predominant type (79.4%). We also found T3 is the most prevalent primary tumour size (32.5%) with prominent lymph node involvement N3 (45.2%), and stage IV (54.8%). Cyclooxygenase-2 overexpression is prevalent among nonkeratinizing squamous cell carcinoma (81.1%), T3 primary tumour size (41.1%), N3 node involvement (60.0%), and IV clinical stage (71.6%). In addition, we found a significant relationship between cyclooxygenase-2 expressions towards tumor size (p < 0.001) and lymph node involvement (p < 0.001) in nasopharyngeal carcinoma.CONCLUSION:It is proved that the overexpression of cyclooxygenase-2 will increase the susceptibility of nasopharyngeal carcinoma patients having advanced primary tumour size and lymph node involvement.

Association of Resistin Gene Polymorphisms with Oral Squamous Cell Carcinoma Progression and Development.

Oral squamous cell carcinoma (OSCC) accounts for over 90% of malignant neoplasms of the mouth. In Taiwan, OSCC is the fourth most common male cancer and the fourth leading cause of male cancer death. Resistin (RETN) is an adipokine that is associated with obesity, inflammation, and various cancers. Here, we examine the association between four single nucleotide polymorphisms (SNPs) of the RETN gene (rs3745367, rs7408174, rs1862513, and rs3219175) and OSCC susceptibility as well as clinical outcomes in 935 patients with OSCC and in 1200 cancer-free healthy controls. We found that, in 1465 smokers, RETN polymorphisms carriers with the betel-nut chewing habit had a 6.708–10.882-fold greater risk of having OSCC compared to RETN wild-type carriers without the betel-nut chewing habit. Patients with OSCC who had A/A homozygous of RETN rs3219175 polymorphism showed a high risk for an advanced tumor size (> T2), compared to those patients with G/G homozygotes. In addition, A/T/G/G haplotype significantly increased the risks for OSCC by 1.376-fold. This study is the first to examine the risk factors associated with RETN SNPs in OSCC progression and development in Taiwan.