miR-211 regulates the expression of RRM2 in tumoral metastasis and recurrence in colorectal cancer patients with a k-ras gene mutation.

Colorectal cancer (CRC) ranks as the third-leading cause of cancer-associated mortalities in Taiwan. The expression of ribonucleotide reductase M2 (RRM2) and p53R2 is associated with tumoral malignancy and progression in several types of cancer. The aim of the present study was to determine the association of p53R2/RRM2 with the upstream expression of microRNA (miR)-211 and the association of expression levels of p53, APC and k-ras with clinical outcomes in patients with CRC. The study consisted of 192 tumor tissue samples obtained from patients with CRC. Immunohistochemistry and direct sequencing of DNA were performed to analyze p53R2/RRM2 protein expression and p53/APC/k-ras gene mutations in these samples. The expression level of miR-211 was detected by reverse transcription-quantitative polymerase chain reaction. The results showed that the expression of p53R2 was lower and that of RRM2 was higher in patients with lymph node metastasis, distant metastasis, and late-stage CRC compared with patients without lymph node metastasis, distant metastasis and early-stage CRC. A high expression of RRM2 in patients had a negative effect on overall survival (OS) and disease-free survival (DFS) in CRC. Positive expression of RRM2 was detected in tumor tissues, and expression associated with the presence of k-ras gene mutation. Furthermore, it was detected that the upstream miR-211 expression was negatively associated with RRM2 expression in tumor tissues of patients with CRC. miR-211 expression was associated with survival and tumoral recurrence in patients with k-ras mutations. The present authors suggest that the downregulation of miR-211 and overexpression of RRM2 in tumor tissues of patients with CRC could be used to predict metastases and disease prognosis, particularly in patients with k-ras gene mutations.

Prediction of type 2 diabetes remission after metabolic surgery: a comparison of the individualized metabolic surgery score and the ABCD score.

BACKGROUND: Metabolic surgery has become increasingly accepted for the treatment of type 2 diabetes (T2D). However, there is limited evidence regarding the optimal candidate and surgical procedure. Although a new individualized metabolic surgery (IMS) score was recently proposed for procedure selection, it has yet to be validated. OBJECTIVE: To validate the IMS score with regard to remission of T2D after metabolic surgery and compare it with the age, body mass index, C-peptide level, and duration of T2D (ABCD) score. SETTING: Hospital-based bariatric center. METHODS: A total of 310 T2D patients who underwent gastric bypass and sleeve gastrectomy at an academic center in Taiwan and had a minimum 5-year follow-up (2004-2012) were examined for the predictive power of complete remission using the IMS and the ABCD scoring systems. RESULTS: At the 5-year follow-up, weight loss was 27.5%, with mean body mass index decreasing from 37.8 to 27.9 kg/m2, mean glycated hemoglobin decreased from 8.6% to 6.1%, and prolonged remission of T2D achieved in 224 (72.3%) T2D patients. Remission rates were higher in patients who underwent gastric bypass than in those who underwent sleeve gastrectomy (73.6% versus 66.1%; P = .04), regardless of T2D severity, and were 96%, 68%, and 16% in patients with IMS mild, moderate, and severe scores, respectively. Although both scores predicted the success of surgery, the ABCD was better in patients with IMS moderate scores. CONCLUSION: Metabolic surgery is an option for T2D patients with obesity. The ABCD score may be better at predicting T2D remission after metabolic surgery compared with the IMS score.

MiR-30c-2* negative regulated MTA-1 expression involved in metastasis and drug resistance of HPV-infected non-small cell lung cancer.

BACKGROUND: MiR-30c-2* is considered to be a tumor suppressor microRNA in various cancers and is associated with gemcitabine sensitivity of lung cancer cells. Downregulation of miR-30c-2* promotes tumor invasion via increased expression of metastasis-associated protein-1. We hypothesized that downregulated expression of miR-30c-2* was involved in human papillomavirus-associated lung tumorigenesis and drug resistance. METHODS: We examined whether expression of human papillomavirus 16/18 oncoprotein and miR-30c-2*-associated genes could be linked to patient outcome by collecting 319 lung tumors from patients with non-small cell lung cancer to determine expression of human papillomavirus 16/18 E6 protein, miR-30c-2*, and miR-30c-2* downstream metastasis-associated protein-1 mRNA by immunohistochemical and real-time polymerase chain reaction analysis. RESULTS: Our results showed that miR-30C-2* levels were increased 45-fold in the E6-knockdown TL-1 cells when compared with levels in the parental cells. More interestingly, metastasis-associated protein-1 expression correlated negatively with miR-30C-2* and positively with human papillomavirus 16 E6 protein expression in lung tumors from lung cancer patients. Metastasis-associated protein-1 expression levels in the tumor tissues correlated positively with tumor stage and nodal metastasis. Patients with high metastasis-associated protein-1 expression, and especially patients infected with human papillomavirus, experienced a poor clinical outcome, tumor recurrence, and a poor therapeutic response compared with those with low metastasis-associated protein-1 expression. CONCLUSION: These results showed that miR-30C-2* and levels of downstream metastasis-associated protein-1 gene expression in the tumor tissues of patients could be useful in predicting clinical outcome and therapeutic response and in selecting useful therapeutic drugs for lung cancer patients, especially patients with human papillomavirus infection.

Environmental exposure and HPV infection may act synergistically to induce lung tumorigenesis in nonsmokers.

Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers.

miR326 maturation is crucial for VEGF-C-driven cortactin expression and esophageal cancer progression.

Esophageal cancer is an aggressive human malignancy with increasing incidence in the developed world. VEGF-C makes crucial contributions to esophageal cancer progression that are not well understood. Here, we report the discovery of regulatory relationship in esophageal cancers between the expression of VEGF-C and cortactin (CTTN), a regulator of the cortical actin cytoskeleton. Upregulation of CTTN expression by VEGF-C enhanced the invasive properties of esophageal squamous cell carcinoma in vitro and tumor metastasis in vivo. Mechanistic investigations showed that VEGF-C increased CTTN expression by downregulating Dicer-mediated maturation of miR326, thereby relieving the suppressive effect of miR326 on CTTN expression. Clinically, expression of Dicer and miR326 correlated with poor prognosis in patients with esophageal cancer. Our findings offer insights into how VEGF-C enhances the robust invasive and metastatic properties of esophageal cancer, which has potential implications for the development of new biomarkers or therapies in this setting.

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

PURPOSE: MiRNAs are small noncoding RNAs that have been implicated in tumor development. They regulate target gene expression either by mRNA degradation or by translation repression. Activation of ß-catenin has been linked to pterygium progression. Here, we hypothesize that ß-catenin-associated miRNA, miRNA-221, and downstream p27Kip1 gene expression are correlated with the pathogenesis of pterygium. METHODS: We collected 120 pterygial and 120 normal conjunctival samples for this study. Immunohistochemistry and real-time reverse transcription (RT)-PCR were performed to determine ß-catenin protein localization, miR-221, and p27Kip1 gene expression. Pterygium cell line (PECs) cell models were used to confirm the effect of ß-catenin, miR-221, and p27Kip1 gene in the proliferation of pterygium cells. RESULTS: Seventy-two (60.0%) pterygial specimens showed high miR-221 expression levels, which was significantly higher than the control groups (13 of 120, 10.8%, p<0.0001). MiR-221 expression was significantly higher in ß-catenin-nuclear/cytoplasmic-positive groups than in ß-catenin membrane-positive and negative groups (p=0.001). We also found that p27Kip1 gene expression in pterygium was negatively correlated with miR-221 expression (p=0.002). In the clinical association, miR-221 expression was significantly higher in the fleshy and intermediate groups than in the atrophic group (p=0.007). The association of miR-221, p27Kip1 and proliferation of pterygium were also confirmed in the PECs model. CONCLUSIONS: Our study demonstrated that activation of ß-catenin in pterygium may interact with miR-221, resulting in p27Kip1 gene downregulation that influences pterygium pathogenesis.

Jejunal Cancer with WRN Mutation Identified from Next-Generation Sequencing: A Case Study and Minireview.

Small bowel cancer is a rare, gastrointestinal cancer originating from the small intestines. Carcinogenesis in the jejunum, the middle segment of the small intestines, occurs less commonly than in the duodenum and ileum. Despite the increasing incidences globally, the cancer is still poorly understood, which includes lack of pathological understanding and etiological reasoning, as it seems to exhibit both similarities and differences with other types of cancers. A 76-year-old Asian man was presented with abdominal pain, which was later attributed to an adenocarcinoma in the jejunum. Initial immunoreactive staining results found no connections to colorectal cancer. The microsatellite instability test was further examined by immunohistochemistry which revealed them to be wild-type. From our exome-capture sequencing results, mutations of WRN may be important as they represent the only genetic defect in this jejunal cancer. The patient has since undergone surgical resection of his cancer and is currently being treated with chemotherapy. The pathology, genomic markers, and treatments are described along with literature review.

Association of p53 codon 72 genotypes and clinical outcome in human papillomavirus-infected lung cancer patients.

BACKGROUND: We recently reported that high-risk human papillomavirus (HPV) 16/18 E6 protein was associated with p53 protein degradation in lung cancer. The present study addressed the relationship between the different p53 genotypes and HPV oncoprotein expression with respect to p53 protein degradation and clinical outcome in primary lung cancer patients. METHODS: We examined whether p53 codon 72 polymorphism and HPV oncoprotein expression could be associated with patients' outcome by collecting 319 lung tumors from patients with non-small cell lung cancer to determine p53 codon 72 polymorphisms, HPV 16/18 infection, and HPV 16/18 E6 and p53 protein expression by polymerase chain reaction (PCR)-restriction fragment length polymorphism, nested-PCR, and immunohistochemical analysis. RESULTS: The presence of HPV 16/18 DNA and E6 protein was inversely associated with p53 expression. The frequency of p53 protein degradation was also much higher in HPV 16/18 E6-positive/Arg/Arg lung tumors than in the other 3 groups. After adjusting gender and tumor type, the major contributors to p53 degradation in lung cancer patients were determined to be p53 codon72 polymorphism and HPV 16/18 E6 oncoprotein expression. This association was not found for HPV 16/18 DNA infection. Survival was significantly longer in patients with HPV 16/18 E6-negative/Arg/Arg tumors (median 32.7 months) than in patients with HPV-positive and p53 genetic variant tumors (p=0.008). CONCLUSIONS: The HPV 16/18 E6 protein, which is involved in the p53 inactivation that contributes to HPV-infected lung tumorigenesis, is associated with the p53 codon 72 genotype. The combination of HPV 16/18 E6 status and p53 codon72 polymorphism in lung tumors is an important biologic and prognostic parameter.

Propolis-induced descending necrotizing mediastinitis and aspiration pneumonia.

Propolis is a resinous substance collected by bees as a sealant for their hives. It is also used in traditional medicine as an antioxidant and antiinflammatory agent to treat ulcers, superficial burns, and microbial diseases. In this report, a 40-year-old woman who took liquid propolis for relief of her common cold experienced severe sore throat, dysphagia, and easy choking followed by fever and chills. Descending necrotizing mediastinitis and concomitant aspiration pneumonia were evident on the image studies. We performed video-assisted thoracoscopic surgery to achieve immediate and adequate drainage, and the patient resumed normal deglutition 2 months later. Early diagnosis and prompt video-assisted thoracoscopic surgery intervention are paramount to manage this life-threatening situation.

Human papillomavirus and non-small cell lung cancer.

Lung cancer is the most common cause of cancer-related deaths in the world, causing more than one million deaths worldwide each year. Human papillomavirus (HPV) are small non-enveloped DNA viruses that infect squamous epithelial cells. Relevant studies have reported lung cancer-related HPV infection rates that fluctuate between 10% and 80%, depending on the various research methods and geographical factors. Various scholars gathered statistics from global research reports and found that 22.4% of the patients with lung cancer presented with an HPV infection, which suggested that HPV infection may relate to the tumorigenesis of non-small cell lung cancer. This article will review the history and discovery of HPV, the correlation between HPV and lung cancer development, and carcinogenesis caused by HPV regulatory genes, such as p53, p21, p16INK4a, and genes related to hypermethylation and genome instability in lung cancer patients with HPV infection. In addition, because studies have highlighted the difference in clinical prognosis for HPV-positive and HPV-negative patients, articles demonstrating the correlation between HPV infection and prognosis for lung cancer patients will be reviewed.

Expression status of ribonucleotide reductase small subunits hRRM2/p53R2 as prognostic biomarkers in stage I and II non-small cell lung cancer.

Overexpression of ribonucleotide reductase M2 (hRRM2) and p53-dependent RR small subunit (p53R2) has been correlated with tumor malignancy and progression in several types of cancer. The aim of this study was to determine the association of p53R2/hRRM2 expression with clinicopathological characteristics of stage I and II non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array that included 92 samples. Correlations between hRRM2 and p53R2 expression and clinicopathological factors, recurrence/metastasis, and outcomes were analyzed. The analyses revealed that there was no correlation between p53R2 expression and clinicopathological factors; hRRM2 was only positively related to poor tumor differentiation (p=0.006). Regarding overall survival during the follow-up period, patients with p53R2+/hRRM2- tumors had the best outcomes (p<0.01). Multivariant Cox analysis revealed that p53R2 (risk=0.232, 95% CI=0.086-0.626, p=0.004) not only served as a prognostic biomarker to predict survival, but also as an independent biomarker to predict disease-free survival (risk=0.545, 95% CI=0.301-0.987, p=0.045) of patients with NSCLC. Therefore, we consider that the expression of p53R2 can be used not only as a biomarker for overall survival, but also as an indicator for tumor recurrence. Based on our finding, p53R2 expression seems more important than that of hRRM2 in prognosis of early-stage lung cancer.

p53R2 expression as a prognostic biomarker in early stage non-small cell lung cancer.

p53R2 is a small subunit of ribonucleotide reductase (RR) which has 80% homology to hRRM2 and metastasis-suppressing potential. Previous reports suggested that the expression of p53R2 is used as a prognostic factor and chemotherapy response indicator in several types of cancer. This study aimed to elucidate the association of p53R2 expression and the clinicopathological characteristics of early stage non-small cell lung cancer (NSCLC). Immunohistochemistry was conducted on a tissue array including 92 early stage NSCLC samples. Correlations between p53R2 and clinicopathological factors, recurrence/metastasis and outcomes were analyzed. The analyses showed that there was no correlation between p53R2 expression and the clinicopathological factors. Among disease-free patients during follow-up, patients with p53R2(+) had a better outcome than those with p53R2(-) (P=0.022). By using Cox multivariate regression analysis, p53R2 (risk factor 3.801; 95% CI 1.004-9.454; P=0.044) served as a prognostic biomarker in the prediction of the survival rate for NSCLC patients. Detection of the RR subunit p53R2 may therefore be a useful prognostic marker in early stage NSCLC.

Lung cancer susceptibility and genetic polymorphism of DNA repair gene XRCC4 in Taiwan.

Non-homologous end-joining (NHEJ) system is a major route in repairing double strand breaks (DSBs), and is important in maintaining the genome stability. The gene XRCC4 is a central role of the NHEJ system, and it is critical in carcinogenesis. In order to reveal the association between XRCC4 and lung cancer, we recruited 164 lung cancer patients and 649 healthy controls from central Taiwan, investigated seven novel polymorphic variants of XRCC4, includes C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317), and analyzed the association of specific genotype with lung cancer susceptibility. The results showed that the XRCC4 G-1394T is significant in Taiwanese lung cancer and the GT genotype of G-1394T is an obvious risk factor of lung cancer susceptibility (P=0.0049), and the G allele is a risky factor (P=0.0087). As for XRCC4 C-1622T (rs7727691), G-652T (rs2075685), C-571T (rs2075686), intron3 DIP (rs28360071), S247A (rs3734091) and intron7 DIP (rs28360317) polymorphism sites, there was no difference in the distribution between the lung cancer and control groups. The analyzing results of joint effect for smoking habit and XRCC4 G-1394T polymorphism was that people with GT genotype and smoking habit present the highest risk of lung cancer than other groups (OR=2.31, 95% CI=1.43-3.72). The G allele of the XRCC4 G-1394T may be responsible for lung carcinogenesis and maybe useful in early detection and prevention of lung cancer.

Lung cancer susceptibility and genetic polymorphisms of Exo1 gene in Taiwan.

AIM: To evaluate the association between the polymorphisms of the Exo1 gene and the risk of lung cancer in central Taiwan. PATIENTS AND METHODS: In this hospital-based study, the association of Exol A-1419G (rs3754093), C-908G (rs10802996), A238G (rs1776177), C498T (rs1635517), K589E (rs1047840), G670E (rs1776148), C723R (rs1635498), L757P (rs9350) and C3114T (rs851797) polymorphisms with lung cancer risk in a central Taiwanese population was investigated. In total, 358 patients with lung cancer and 358 age- and gender-matched healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped. RESULTS: A significantly different distribution was found in the frequency of the Exo1 K589E genotype, but not the other genotypes, between the lung cancer and control groups. The A allele Exo1 K589E conferred a significantly (p = 0.0097) increased risk of lung cancer. As for the rest of the polymorphisms, there was no difference in distribution between the lung cancer and control groups. Gene environment interactions with smoking were significant for Exo1 K589E polymorphism. The Exo1 K589E AG and AA genotype in association with smoking conferred an increased risk of 1.7208 (95% confidence interval = 1.2188-2.4295) for lung cancer. CONCLUSION: Our results provide the first evidence that the A allele of Exo1 K589E may be associated with the development of lung cancer and may be a novel useful marker for primary prevention and anticancer intervention.

Association between expression of human papillomavirus 16/18 E6 oncoprotein and survival in patients with stage I non-small cell lung cancer.

The clinical significance of HPV-16/18 E6 oncoprotein expression in non-small cell lung cancer (NSCLC) is not fully known. A study was undertaken to investigate the association between expression of human papillomavirus 16/18 E6 oncoprotein and survival in patients with stage I NSCLC. We analyzed a series of 217 patients with stage I NSCLC for the presence of HPV-16/18 E6 oncoprotein by immunohistochemistry. HPV-16 E6 oncoprotein was expressed in 49 (22.6%) patients and HPV-18 E6 oncoprotein was expressed in 31 (14.3%) patients. Statistical analysis revealed that the prevalence of expression of HPV-16 and HPV-18 E6 oncoproteins was significantly high in female patients, nonsmokers and patients with adenocarcinoma. The adjusted odds ratio for expression of HPV-16 E6 oncoprotein in female patients was 2.275 [95% confidence interval (CI), 0.999-5.179] and that in patients with adenocarcinoma was 2.320 (95% CI, 1.029-5.232). These ratios were significantly higher than those in male patients and patients with squamous cell carcinoma. Interestingly, we found that the 17 patients who expressed HPV-16 and HPV-18 E6 oncoprotein had a higher 5-year cumulate survival rate (72.2%) than the 154 patients who did not express both oncoproteins (48.3%); the difference was significant (p=0.055). Expression of HPV-16/18 E6 oncoprotein in stage I NSCLC may play an important role in female adenocarcinoma patients and survival benefits in patients who expressed HPV-16 and HPV-18 E6 oncoprotein.

A novel single nucleotide polymorphism in XRCC4 gene is associated with gastric cancer susceptibility in Taiwan.

BACKGROUND: The DNA repair gene XRCC4, an important caretaker of the overall genome stability, is thought to play a major role in the human carcinogenesis. We investigate some novel and important polymorphic variants of XRCC4, at codon 247 (rs3734091), G-1394T (rs6869366), intron 3 (rs28360071), and intron 7 (rs28360317), of their associated with gastric cancer susceptibility. MATERIALS AND METHODS: In this hospital-based case-control study, the association of XRCC4 polymorphisms with gastric cancer risk in a Taiwanese population was investigated. In total, 121 patients with gastric cancer and 121 age-matched healthy controls recruited were genotyped investigating these polymorphisms' association with gastric cancer susceptibility. RESULTS: We found a significant difference in the frequency of the XRCC4 G-1394T genotype, but not others, between the gastric cancer and control groups. Those who had G/T or G/G at XRCC4 G-1394T showed a 3.79-fold (95% confidence interval = 1.47-9.82) increased risk of gastric cancer compared to those with T/T. As for XRCC4 codon 247, intron 3, or intron 7, there was no difference in distribution between the gastric cancer and control groups. CONCLUSIONS: Our findings suggest that the G allele of the XRCC4 G-1394T may contribute to gastric carcinogenesis and may be useful for gastric cancer early detection and prevention.

Prognostic significance of expression of nm23-H1 and focal adhesion kinase in non-small cell lung cancer.

nm23-H1, a nucleoside diphosphate kinase (NDPK), enhances drug sensitivity and has antimetastatic activity, whereas focal adhesion kinase (FAK) is closely associated with cell migration and tumour spreading. The relationship between these two proteins, however, is not well elucidated. In this study, we investigate their correlation in patients with non-small cell lung cancer (NSCLC). Expressions of nm23-H1 and FAK were examined by reverse transcription-polymerase chain reaction and immunoblotting in surgical resections. The relationship between these two genes was assessed statistically. Patients were classified into four groups according to the expression of nm23-H1 and FAK by immunohistochemistry: FAK-negative/nm23-H1-positive, FAK-negative/nm23-H1-negative, FAK-positive/nm23-H1-positive and FAK-positive/nm23-H1-negative. Although the causal correlation is still uncertain, our results showed that protein expression of nm23-H1 was inversely correlated with that of FAK. The combined analysis of nm23-H1 and FAK protein expression in the same tumour specimens revealed that patients with FAK-negative/nm23-H1-positive tumours survived the longest, 56 months, among those with nm23-H1 and FAK features (P<0.001). Our data indicate that expressions of nm23-H1 and FAK are inversely correlated. These results suggest that the status of nm23-H1 and FAK protein expression may help in predicting the aggressive behavior of NSCLC. However, further studies are warranted to clarify the impact of FAK on the function of nm23-H1 as an anti-metastatic gene.

Revisit of 1997 TNM staging system--survival analysis of 1112 lung cancer patients in Taiwan.

BACKGROUND: There is neither a nation-wide nor a large-scale, multi-institutional lung cancer database available for stage-by-stage survival analysis in Taiwan at present. METHODS: Using the data element provided by the International Association for the Study of Lung Cancer, the Taiwan Lung Cancer Society initiated a project to include native lung cancer patients into a global database. A total of 1112 Taiwan lung cancer patients treated in 7 medical centers were enrolled. RESULTS: In small cell lung cancer, patients with ipsilateral pleural effusion had a survival between those with locoregional disease alone and those with distant metastasis; however, the difference was not statistically significant (P = 0.204). In non-small cell lung cancer, tumor size had significant survival influence for patients as a whole (P < 0.001) but it did not support the further division of stage IA according to tumor size (P = 0.122). The survival was compatible in stage IIIB and IV patients and therefore, the survival impact of pleural effusion cannot be determined. In patients with pIIIA-N2 disease, those who had station 8 nodal metastasis had inferior survival (P = 0.020) and station 5 superior survival (P = 0.010). In patients with distant metastasis, bone, liver, or distant lymph node metastasis predicted an inferior survival (all P values < 0.05). CONCLUSIONS: The present study provides for comparison in this area a stage-by-stage reference for the survival of lung cancer patients. Some factors other than current TNM descriptors need to be further investigated in constructing the next version of the staging system.