Quantitative proteomic analysis of bronchoalveolar lavage fluids from patients with small cell lung cancers.

PURPOSE: Small cell lung cancer (SCLC) is one of the malignant cancers with aggressive progression and poor prognosis. Bronchoalveolar lavage fluid (BALF) has been arising recently as a potential source of biomarkers for lung cancers. In this study, we performed quantitative BALF proteomic analysis to identify potential biomarkers for SCLC. EXPERIMENTAL DESIGN: BALF were collected from tumor-bearing lungs and non-tumor lungs of five SCLC patients. Then, BALF proteomes were prepared for a TMT-based quantitative mass spectrometry analysis. Differentially expressed proteins (DEP) were identified when considering individual variation. Potential SCLC biomarker candidates were validated by immunohistochemistry (IHC). A public database of multiple SCLC cell lines was used to evaluate the correlation of these markers with SCLC subtypes and chemo-drug responses. RESULTS: We identified 460 BALF proteins in SCLC patients and observed considerable individual variation among the patients. Immunohistochemical analysis and bioinformatics resulted in the identification of CNDP2 and RNPEP as potential subtype markers for ASCL1 and NEUROD1, respectively. In addition, CNDP2 was found to be positively correlated with responses to etoposide, carboplatin, and irinotecan. CONCLUSIONS AND CLINICAL RELEVANCE: BALF is an emerging source of biomarkers, making it useful for the diagnosis and prognosis of lung cancers. We characterized the proteomes of paired BALF samples collected from tumor-bearing and non-tumor lungs of SCLC patients. Several proteins were found elevated in tumor-bearing BALF, and especially CNDP2 and RNPEP appeared to be potential indicators for ASLC1-high and NEUROD1-high subtypes of SCLC, respectively. The positive correlation of CNDP2 with chemo-drug responses would help to make decisions for treatment of SCLC patients. These putative biomarkers could be comprehensively investigated for a clinical use towards precision medicine.

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy.

This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients' subgroup warranting tailored therapeutic approaches.

Triple primary lung cancer: a case report.

BACKGROUND: The risk of developing lung cancer is increased in smokers, patients with chronic obstructive pulmonary disease, individuals exposed to environmental carcinogens, and those with a history of lung cancer. Automobile exhaust fumes containing carcinogens are a risk factor for lung cancer. However, we go through life unaware of the fact that automobile exhaust is the cause of cancer. Especially, in lung cancer patient, it is important to search out pre-existing risk factors and advice to avoid them, and monitor carefully for recurrence after treatment. CASE PRESENTATION: This is the first report of a case with triple lung cancers with different histologic types at different sites, observed in a 76-year-old parking attendant. The first adenocarcinoma and the second squamous cell carcinoma were treated with stereotactic radiosurgery because the patient did not want to undergo surgery. Although the patient stopped intermittent smoking after the diagnosis, he continued working as a parking attendant in the parking lot. After 29 months from the first treatment, the patient developed a third new small cell lung cancer; he was being treated with chemoradiation. CONCLUSIONS: New mass after treatment of lung cancer might be a multiple primary lung cancer rather than metastasis. Thus, precision evaluation is important. This paper highlights the risk factors for lung cancer that are easily overlooked but should not be dismissed, and the necessity of discussion with patients for the surveillance after lung cancer treatment. We should look over carefully the environmental carcinogens already exposed, and counsel to avoid pre-existing lung cancer risk factors at work or residence in patients with lung cancer.

Role of the WNT/ß-catenin/ZKSCAN3 Pathway in Regulating Chromosomal Instability in Colon Cancer Cell lines and Tissues.

Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) acts as an oncogenic transcription factor in human malignant tumors, including colon and prostate cancer. However, most of the ZKSCAN3-induced carcinogenic mechanisms remain unknown. In this study, we identified ZKSCAN3 as a downstream effector of the oncogenic Wnt/ß-catenin signaling pathway, using RNA sequencing and ChIP analyses. Activation of the Wnt pathway by recombinant Wnt gene family proteins or the GSK inhibitor, CHIR 99021 upregulated ZKSCAN3 expression in a ß-catenin-dependent manner. Furthermore, ZKSCAN3 upregulation suppressed the expression of the mitotic spindle checkpoint protein, Mitotic Arrest Deficient 2 Like 2 (MAD2L2) by inhibiting its promoter activity and eventually inducing chromosomal instability in colon cancer cells. Conversely, deletion or knockdown of ZKSCAN3 increased MAD2L2 expression and delayed cell cycle progression. In addition, ZKSCAN3 upregulation by oncogenic WNT/ß-catenin signaling is an early event of the adenoma-carcinoma sequence in colon cancer development. Specifically, immunohistochemical studies (IHC) were performed using normal (NM), hyperplastic polyps (HPP), adenomas (AD), and adenocarcinomas (AC). Their IHC scores were considerably different (61.4 in NM; 88.4 in HPP; 189.6 in AD; 246.9 in AC). In conclusion, ZKSCAN3 could be responsible for WNT/ß-catenin-induced chromosomal instability in colon cancer cells through the suppression of MAD2L2 expression.

Pulmonary Metastasizing Low-Grade Endometrial Stromal Sarcoma: Case Report and Review of Diagnostic Pitfalls.

Pulmonary manifestations of benign metastasizing leiomyoma (BML) usually include multiple well-defined, round, bilateral nodules. Low-grade endometrial stromal sarcoma (LG-ESS) is a rare uterine tumor. A 70-year-old woman visited the clinic complaining of acute cough and dyspnea in April 2017. Chest computed tomography (CT) revealed pneumothorax and multiple pulmonary nodules. She had a history of hysterectomy for uterine leiomyoma 23 years ago. Biopsy revealed that the pulmonary masses were consistent with BML. However, the patient had two subsequent episodes of acute, recurrent respiratory distress, accompanied by massive pleural effusions and hydropneumothorax over the next two years. A chest CT performed for acute dyspnea revealed large and multiple hydropneumothoraces. The size and distribution of pulmonary masses were aggravated along with cystic changes and bilateral pleural effusions. Given this aggressive feature, additional immunohistochemical findings and gynecologic pathologist review confirmed the correct diagnosis to be LG-ESS. After initiating anti-estrogen therapy, the patient achieved a partial response, without recurrence of symptoms, for 28 months. Metastatic LG-ESS responds well to anti-hormonal therapy. If the clinical pattern of a disease is different than expected, the possibility of a correction in the diagnosis should be considered.

Clinicopathologic and Genetic Features of Primary T-cell Lymphomas of the Central Nervous System: An Analysis of 11 Cases Using Targeted Gene Sequencing.

Primary central nervous system lymphoma (PCNSL) of peripheral T-cell lineage (T-PCNSL) is rare, and its genetic and clinicopathologic features remain unclear. Here, we present 11 cases of T-PCNSL in immunocompetent individuals from a single institute, focusing on their genetic alterations. Seven cases were subject to targeted panel sequencing covering 120 lymphoma-related genes. Nine of the eleven cases were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), of which one was of γδT-cell lineage. There was one case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma and another of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) of αßT-cell lineage. The male to female ratio was 7 : 4 and the age ranged from 3 to 75 years (median, 61 y). Most patients presented with neurological deficits (n=10) and showed multifocal lesions (n=9) and deep brain structure involvement (n=9). Tumor cells were mostly small-to-medium, and T-cell monoclonality was detected in all nine evaluated cases. PTCL-NOS was CD4-positive (n=4), CD8-positive (n=3), mixed CD4-positive and CD8-positive (n=1), or CD4/CD8-double-negative (n=1, γδT-cell type). Cytotoxic molecule expression was observed in 4 (67%) of the 6 evaluated cases. Pathogenic alterations were found in 4 patients: one PTCL-NOS case had a frameshift mutation in KMT2C, another PTCL-NOS case harbored a truncating mutation in TET2, and another (γδT-cell-PTCL-NOS) harbored NRAS G12S and JAK3 M511I mutations, and homozygous deletions of CDKN2A and CDKN2B. The ENKTL (αßT-cell lineage) case harbored mutations in genes ARID1B, FAS, TP53, BCOR, KMT2C, POT1, and PRDM1. In conclusion, most of the T-PCNSL were PTCL-NOS, but sporadic cases of other subtypes including γδT-cell lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and ENKTL were also encountered. Immunophenotypic analysis, clonality test, and targeted gene sequencing along with clinicoradiologic evaluation, may be helpful for establishing the diagnosis of T-PCNSL. Moreover, this study demonstrates genetic alterations with potential diagnostic and therapeutic utility in T-PCNSL.

Overexpression of Reactive Oxygen Species Modulator 1 Predicts Unfavorable Clinical Outcome in EGFR-Mutant Lung Adenocarcinomas Treated With Targeted Therapy.

PURPOSE: Reactive oxygen species modulator 1 (Romo1) is a novel protein that regulates the production of intracellular reactive oxygen species. Romo1 has been shown to be associated with poor survival in various clinical settings for the treatment of lung cancer. In this study, we evaluated whether tissue Romo1 expression was associated with clinical outcomes in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma treated with tyrosine kinase inhibitors (TKIs). METHOD: Romo1 expression in tumor tissues was examined by immunohistochemistry and evaluated by histologic score. Univariate and multivariate analyses were performed to identify the clinicopathologic parameters, including Romo1 expression, which may be associated with progression-free survival (PFS), overall survival (OS), and incidence of secondary T790M mutation. RESULTS: A total of 96 tumor specimens were analyzed. With the cut-off value of 200, 71 (74.0%) and 25 (26.0%) patients were classified into low and high Romo1 groups, respectively. The median PFS of the high Romo1 group was significantly shorter than that of the low Romo1 group (13.1 vs 19.9 months, p = 0.0165). The median OS of the high Romo1 group was also significantly shorter than that of the low Romo1 group (19.8 vs 37.0 months, p = 0.0006). Multivariate analyses showed that high Romo1 expression was independently associated with both poor PFS (hazard ratio [HR] = 2.48, 95% confidence interval [CI]: 1.35-4.56, p = 0.0034) and poor OS (HR = 3.17, 95% CI: 1.57-6.41, p = 0.0013). In addition, the rate of secondary T790M mutation after TKI failure was significantly lower in the high Romo1 group than the low Romo1 group (16.7% vs. 38.3%, p = 0.0369). CONCLUSIONS: Romo1 overexpression was associated with poor response to treatment and short survival in patients treated with EGFR-TKIs, suggesting a distinct subgroup warranting active surveillance and tailored therapeutic approach. In addition, our data highlight that Romo1 could be a potential predictive and prognostic biomarker for this patient population.

Low H3K9me3 Expression Is Associated With Poor Prognosis in Patients With Distal Common Bile Duct Cancer.

BACKGROUND/AIM: Histone modification is associated with tumorigenesis and cancer progression. Recent studies have revealed the prognostic value of histone modification; however, its prognostic role in distal bile duct cancer remains unclear. PATIENTS AND METHODS: We analyzed the expression of H3K9me3, H4K20me3, and H3K36me3 and its correlation with survival outcomes in resected samples from 88 patients with distal bile duct cancer. RESULTS: Low expression rates of H3K9me3, H4K20me3, and H3K36me3 were significantly associated with poor overall survival (p=0.003, 0.008, and 0.047, respectively) and event-free survival (p=0.03 for H3K9m3). Additionally, low-expression of H3K9me3 was an independent poor prognostic indicator (p<0.001; HR=7.85; 95% CI=2.693-22.883). CONCLUSION: H3K9me3 was an independent poor prognostic factor in distal common bile duct cancer. Our results suggest that histone markers are potential prognostic markers and provide better management for patients at risk for an aggressive course of disease.

Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study.

PURPOSE: It has been reported that the overexpression of reactive oxygen species modulator 1 (Romo1) is significantly associated with poor survival outcomes in patients with lung cancer who received surgical resection, conventional fractionated radiotherapy, and chemotherapy. In this study, we investigated whether Romo1 expression is associated with survival outcomes in patients with early-stage lung cancer who were treated with radiosurgery. METHODS: Romo1 protein expression was evaluated and scored in the tumor tissue specimens of 40 patients with non-small cell lung cancer by immunohistochemistry. An optimal cut-off for Romo1 expression was determined and used to allocate patients to low or high Romo1 expression groups. Survival outcomes were compared between the two groups. RESULTS: Romo1 expression was significantly associated with distant metastasis-free survival. The 1- and 2-year distant metastasis-free survival rates were 96.4% and 92.6% in the low Romo1 expression group and 87.5% and 46.7% in the high Romo1 expression group (P=0.041), respectively. The overall, local recurrence-free, regional recurrence-free, and disease progression-free survival rates were higher in the low Romo1 expression group than the high Romo1 expression group. However, the differences were not statistically significant. CONCLUSION: Romo1 overexpression is associated with poor distant metastasis-free survival in patients with non-small cell lung cancer treated with radiosurgery. Further, large-scale prospective studies are required to identify the clinical efficacy of Romo1 as a potential adverse prognostic factor in lung cancer.

Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change.

Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.

Adenocarcinoma and Neuroendocrine Collision Tumor in a Giant Gastric Hyperplastic Polyp.

Screening esophagogastroduodenoscopy of a 65-year-old man revealed a 4.7-cm polypoid in the gastric high body. Clinical and laboratory findings, including serum gastrin level (460 pg/mL) and biopsy findings, were consistent with a diagnosis of type I neuroendocrine tumor (NET). Histologically, the mass consisted of dilated tortuous glands at the surface and grade 1 NET in deeper tissue. Some hyperplastic glands exhibited a transition to adenocarcinoma, which invaded the NET, simulating a "tumor in tumor" appearance. Next-generation sequencing revealed that the adenocarcinoma component harbored a TP53 mutation, whereas the NET component showed no pathogenic mutation. To our knowledge, this unusual collision of adenocarcinoma and NET within a single gastric hyperplastic polyp has not been previously described. This case suggests that large gastric hyperplastic polyps should be carefully examined because of the possibility of underlying NET and malignant transformation of surface epithelium.

Inhibition of Carbonyl Reductase 1 Enhances Metastasis of Head and Neck Squamous Cell Carcinoma through ß-catenin-Mediated Epithelial-Mesenchymal Transition.

Objective: Human carbonyl reductase 1 (CBR1) plays key roles in the regulation of oxidative stress and tumor progression. However, the detailed mechanism and clinical correlation between CBR1 and tumor progression in head and neck squamous cell carcinoma (HNSCC) is largely unexplored. This study will focus the effects of CBR1 on head and neck cancer progression and explore the possible mechanisms. Materials and Methods: CBR1 mRNA expression was analyzed according to lymph node metastasis (LNM) status in patients with HNSCC from publicly available databases. CBR1 protein levels were measured and compared in HNSCC patient tissues, with or without metastasis, using immunohistochemistry (IHC). The invasive ability of HNSCC with modulated CBR1 expression was assayed using an invasion assay. Expression levels of EMT marker proteins were analyzed using immunoblotting. Results: HNSCC patients with LNM showed lower expression of CBR1 than those without LNM. In addition, IHC in tissues indicated that patients with LNM had relatively lower levels of CBR1 in cancer tissue. Consistently, in vitro invasion assay, we found that CBR1 inhibition using specific short interfering RNA treatment resulted in two- to three-fold increased invasion ability of HNSCC cell lines. Also, we proved that depletion of CBR1 activated marker proteins participating in epithelial-mesenchymal transition (EMT) signaling. CBR1 inhibition increased levels of intracellular reactive oxygen species (ROS) in HNSCC cells leading to upregulation of ß-catenin, one of main transcription factors that induce EMT-related genes. Conclusion: Our findings suggested that CBR1 plays an important role in metastasis of HNSCC tumors via regulation of ROS-mediated ß-catenin activity, and that CBR1 may be marker for progression of HNSCC to metastasis.

Stage IV Epstein-Barr Virus-Associated Early Gastric Cancer and Comparative Analysis of Genetic Alterations in Primary and Metastatic Tumors.

Early gastric cancer (EGC) with synchronous distant metastasis is extremely rare. Here, we report a case of stage IV Epstein-Barr virus (EBV) -associated EGC. A 51-year-old man presented with vague abdominal pain of 3 weeks' duration. Imaging studies revealed enlargement of the left supraclavicular, perigastric, and para-aortic lymph nodes, a huge gastric polypoid mass, and multiple liver masses. Histopathological examination of a biopsy specimen of the supraclavicular lymph node showed poorly differentiated carcinoma expressing EBV in tumor cell nuclei. The gastric mass exhibited tubular adenocarcinoma, which also expressed EBV in tumor cell nuclei. After 3 weeks of palliative chemotherapy with fluoropyrimidine and platinum, the patient died of liver failure. Next-generation sequencing analysis revealed mutation of the CDKN1B gene in the metastatic carcinoma and mutations of the CTNNB1 and PIK3R1 genes in the gastric carcinoma. In addition to the rare presentation of EBV-associated EGC, this case showed marked morphological and molecular differences between primary and metastatic tumors, which suggests clonal evolution of EBV-associated GC.

Clinicoradiological Features of Recurrent Meningioma With High Grade Transformation.

BACKGROUND/AIM: A minority of grade I meningiomas (MG1s) recur after surgical resection and their progression is associated with high grade transformation (HGT). This study aimed to characterize the clinicoradiological features of recurrent MGs (RMG) with HGT. PATIENTS AND METHODS: We identified 17 patients diagnosed with MG1 who then underwent surgery for RMG. Patients were categorized into HGT group vs. non-HGT (nHGT) group based on RMG histological grade and clinicoradiological features were comparatively analyzed. RESULTS: HGT was observed in 41.4% of RMGs. Original tumor size was larger in the HGT group and recurrence time interval was shorter. Following recurrence, 57.1% in the HGT group experienced further disease progression, compared to 22.2% in the nHGT group. CONCLUSION: A considerable HGT rate in RMGs developed after MG1 was observed. Although HGT was not distinguished from nHGT by radiological features, HGT in RMG was associated with larger initial tumor size and shorter recurrence time interval.

Reactive Oxygen Species Modulator 1 As An Adverse Prognostic Marker In Stage III Non-Small Cell Lung Cancer Treated With Radiotherapy: A Retrospective Pilot Study.

PURPOSE: Reactive oxygen species modulator 1 (ROMO1) is a novel protein regulating intracellular reactive oxygen species production. Although increased ROMO1 expression has been associated with poor clinical outcomes in several human malignancies, the clinical implication of this protein in a radiotherapy setting has never been explored. The aim of this study was to investigate whether ROMO1 expression is associated with survival in lung cancer patients who received radiotherapy. METHODS: ROMO1 protein expression was evaluated immunohistochemically using histologic score (H-score) in 49 tumor tissues from stage III non-small cell lung cancer (NSCLC) patients treated with definitive radiotherapy. We performed survival analyses according to various clinicopathological parameters including ROMO1 expression. RESULTS: ROMO1 expression was not associated with any clinicopathological parameter of age, sex, smoking status, stage, or histological subtype. Multivariate analyses showed that high ROMO1 expression was independently associated with worse progression-free survival (hazard ratio [HR] = 1.87, 95% confidence interval [CI]: 1.02-4.23) and with worse overall survival (HR = 2.79, 95% CI:1.13-6.87). In addition, high ROMO1 expression was independently associated with shorter time to loco-regional recurrence (HR=2.71, 95% CI:1.04-6.28) but was not associated with time to distant metastasis. CONCLUSION: ROMO1 overexpression was associated with early loco-regional recurrence and poor survival outcomes in stage III NSCLC treated with definitive radiotherapy. Our exploratory results provide a basis for further large-scale studies to validate whether ROMO1 could be a prognostic marker in this setting.

Tumor-specific Expression of Insulin-like Growth Factor II mRNA-binding Protein 3 Independently Predicts Worse Survival of Patients With Adenocarcinoma of the Ampulla of Vater.

BACKGROUND/AIM: Insulin-like growth factor II mRNA-binding protein 3 (IMP3) plays an important role in the adhesion, invasion, and metastasis of tumor cells. Although emerging evidence suggests that IMP3 promotes tumor progression in several malignancies, the expression of IMP3 and its prognostic implication in adenocarcinoma of the ampulla of Vater (AVAC) has not been clarified to date. MATERIALS AND METHODS: The IMP3 expression status in 87 AVAC tissues was examined using immunostaining, and its association with various clinicopathological features and outcome of patients with AVAC was investigated. RESULTS: The vast majority (87.4%) of AVAC cases displayed at least focal cytoplasmic and membranous IMP3 immunoreactivity in tumor cells, whereas IMP3 expression was consistently absent from normal biliary epithelial cells. Tumor-specific IMP3 expression was associated with submucosal and pancreatic invasion, which were not identified in the corresponding hematoxylin and eosin-stained slides. This finding led to up-staging of the pathological tumor stage in two cases of well-differentiated AVAC. In addition, high IMP3 expression was significantly associated with a poorly differentiated histology (p=0.026). Survival analyses revealed that high IMP3 expression independently predicted shorter recurrence-free (p=0.003) and overall (p=0.029) survival. CONCLUSION: Our study demonstrated tumor-specific IMP3 expression in AVAC, which will be helpful in determining invasion depth and tumor extent in patients with well-differentiated tumors, as well as indicating worse survival of patients with AVAC. Our data highlight IMP3 expression status as a potential diagnostic and prognostic marker for AVAC.

Lower Sympathetic Nervous System Density and ß-adrenoreceptor Expression Are Involved in Gastric Cancer Progression.

BACKGROUND/AIM: Identifying the role of the sympathetic nervous system (SNS) in tumor progression is among the most important challenges in cancer research. This study aimed to investigate the role of the SNS and ß-adrenoreceptor in gastric cancer progression. MATERIALS AND METHODS: The density of SNS was quantified by immunohistochemical staining for tyrosine hydroxylase in 115 surgically-resected gastric cancer specimens. Immunostaining for ß1- and ß2-adrenoreceptor was also performed to examine the ß-adrenoreceptor expression status in gastric cancer. Then the association of protein expression status with histological grade, pathological tumor stage (pT), and pathological node stage of gastric cancer was investigated. RESULTS: The SNS density of pT4 tumors was significantly lower than that of pT1-3 tumors. The SNS density was positively correlated with ß1-adrenoreceptor expression status. In addition, lower ß1-adrenoreceptor expression was significantly associated with increased lymph node metastasis. Reduced ß2-adrenoreceptor staining proportion was significantly associated with worse histological grade. Furthermore, the proportion of ß2-adrenoreceptor staining was significantly lower in tumors with diffuse-type histology, than those with intestinal-type histology. CONCLUSION: A lower SNS density and ß-adrenoreceptor expression was associated with an aggressive oncogenic behavior including worse histological grade, advanced pT, and increased lymph node metastasis. SNS and ß-adrenergic pathway are involved in the negative regulation of gastric cancer progression.

Carbonyl reductase 1 is a new target to improve the effect of radiotherapy on head and neck squamous cell carcinoma.

BACKGROUND: Human carbonyl reductase 1 (CBR1) plays major roles in protecting cells against cellular damage resulting from oxidative stress. Although CBR1-mediated detoxification of oxidative materials increased by stressful conditions including hypoxia, neuronal degenerative disorders, and other circumstances generating reactive oxide is well documented, the role of CBR1 under ionising radiation (IR) is still unclear. METHODS: The formalin-fixed and paraffin-embedded tissues of 85 patients with head and neck squamous cell carcinoma (HNSCC) were used to determine if CBR1 expression effects on survival of patients with treatment of radiotherapy. Subsequently colony formation assays and xenograft tumor mouse model was used to verify the relationship between CBR1 expression and radiosensitivity in HNSCC cells. Publicly-available data from The Cancer Genome Atlas (TCGA) was analysed to determine if CBR1 expression affects the survival of patients with HNSCC. To verify CBR1-mediated molecular signalling pathways, cell survival, DNA damage/repair, reactive oxygen species (ROS), cell cycle distribution and mitotic catastrophe in HNSCC cells with modulated CBR1 expression by knockdown or overexpression were measured using by colony formation assays, flow cytometry, qRT-PCR and western blot analysis. RESULTS: HNSCC patients with low CBR1 had a significantly higher survival rate than the high CBR1 expression (84.2% vs. 57.8%, p = 0.0167). Furthermore, HNSCC patients with low CBR1 expression showed a good prognosis for IR compared to patients with highly expressed CBR1. Also, we found that IR upregulated CBR1 mRNA via Nrf2 activation in HNSCC cells and patients. In vitro analysis, we found that CBR1-specific siRNA or inhibitor significantly enhanced radiosensitivity after IR, while CBR1 overexpression decreased. CBR1 inhibition by siRNA or inhibitor treatment accumulated cellular ROS leading to aberrant DNA damage repair and an increase of mitotic catastrophe. Moreover, the combination of CBR1 depletion with IR dramatically inhibited primary tumour growth in a xenograft tumor mouse model. CONCLUSION: Our findings indicate that CBR1 has a key role in DNA damage response through regulation of IR-mediated ROS generation. Consistently, CBR1 expression is highly correlated with patient survival after and susceptibility to radiation therapy. Therefore, CBR1 inhibition with IR might be a potent therapeutic strategy for HNSCC treatment.