• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1391-1396
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• 2014

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the most common cause of lung cancer death. Currently, the epidermal growth factor receptor inhibitor gefitinib is used for its treatment; however, drug resistance is a major obstacle. Expression of Met has been associated with both primary and acquired resistance to gefitinib, but the mechanisms regulating its expression are not fully understood. Recently, miRNAs such as miR-130a have been shown to play a role in gefitinib resistance, but importance in NSCLC and relationships with Met have not been fully explored. Here we show that miR-130a is over-expressed in gefitinibsensitive NSCLC cell lines, but is low in gefitinib-resistant NSCLC cell lines. Moreover, miR-130a expression was negatively correlated with that of Met. Further analysis revealed that over-expression of miR-130a increased cell apoptosis and inhibited proliferation of NSCLC cells treated with gefitinib, whereas lowering the expression of miR-130a decreased cell apoptosis and promoted cell proliferation after treatment with gefitinib in both gefitinib-sensitive and -resistant NSCLC cell lines, suggesting that miR-130a overcomes gefitinib resistance. We also demonstrated that miR-130a binds to the 3'-UTR of Met and significantly suppresses its expression. Finally, our results showed that over-expressing Met could "rescue" the functions of miR-130a regarding cell apoptosis and proliferation after cells are treated with gefitinib. These findings indicate that the miR-130a/Met axis plays an important role in gefitinib resistance in NSCLC. Thus, the miR-130a/Met axis may be an effective therapeutic target in gefitinib-resistant lung cancer patients.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4759-4768
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• 2015

Background: Several studies have investigated predictive and prognostic biomarkers for patients treated with anti-epidermal growth factor receptor (EGFR) agents in lung cancer. However, the conclusion is controversial. Materials and Methods: A meta-analysis was conducted to evaluate the associations of mutant K-ras, PIK3CA and PTEN deficiency with the efficacy of anti-EGFR agents in lung cancer. The primary endpoint was objective response rate (ORR). The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results: A total of 61 studies were included in the final meta-analysis. The result showed that K-ras mutation was a good predictor for ORR (RR=0.42, 95%CI, 0.33-0.55, p=0.000) and an effective prognostic marker for OS (HR=1.37, 95%CI, 1.15-1.65, p=0.001) and PFS (HR=1.33, 95%CI, 1.05-1.69, p=0.019). However, PTEN deficiency or PIK3CA mutation did not show any significance predictive value for ORR (PTEN, RR=0.82, 95%CI, 0.56-1.19, p=0.286; PIK3CA, RR=1.08, 95%CI, 0.17-6.66, P=0.938). And PTEN deficiency or expression of PIK3CA did not show significance prognostic value for OS (PTEN, HR=0.88, 95%CI, 0.31-2.46,P=0.805; PIK3CA, HR=0.79, 95%CI: 0.23-2.68, P=0.706). Conclusions: Our meta-analysis showed that K-ras mutation may be an effective predictor in lung cancer patients treated with anti-EGFR agents. Whereas, the predictive and prognostic value of PTEN deficiency and PIK3CA mutation need to be further investigated.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.3
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• pp.1787-1790
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• 2013

This study evaluated the effects of ZD1839, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, on nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Influence of ZD1839 alone or combined with cisplatin on the NPC cell line CNE2 was detected by MTT assay with flow cytometry assessment of cell cycle distribution and apoptosis rates. Nude mice NPC xenografts were also used to evaluate the effects of ZD1839 alone or combined with cisplatin. The Student's t test evaluated statistical significance. ZD1839 alone or combined with cisplatin inhibited CNE2 cell line proliferation. ZD1839 induced CNE2 cell cycle arrest in the G1 phase, and higher concentrations induced apoptosis. Xenograft tumors were significantly smaller when treated with 200 mg/kg ZD1839, cisplatin, or cisplatin combined with 100 mg/kg ZD1839 than untreated controls. ZD1839 (200 mg/kg) alone showed good tumor inhibition effects, reduction of tumor weights, and smaller tumor volume without loss of body weight. ZD1839 (200 mg/kg) might provide a good and effective therapeutic reagent for NPC.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3903-3909
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• 2016

Purpose: To evaluate the expression of Her2/neu and Ki-67 in benign and malignant gallbladder lesions, and to establish correlations with clinico-pathologic parameters. Materials and Methods: A retrospective analysis was conducted on formalin fixed paraffin embedded (FFPE) benign (n=25) and malignant gallbladder (n=25) tissue samples. Hematoxylin and eosin stained slides of each case were reviewed for: type of malignancy (whether adenocarcinoma, squamous cell carcinoma, or any other type), grade (well, moderate, and poor), depth of invasion, pre-neoplastic changes in adjacent mucosal epithelium like metaplasia and dysplasia. Immunohistochemistry for Her 2 neu and Ki-67 was performed and data analysis was conducted using SPSS 17 software. Chi-square test was used to compare categorical/dichotomous variables. P value of ${\leq}0.05$ was considered significant. Results: The difference of Her 2 neu expression and Ki67 index between benign and malignant groups was found to be statistically significant. Her2/neu positivity did not have any significant correlation with various clinicopathological parameters other than liver involvement. 5 cases of gallbladder cancer showed both Her2/neu and Ki67 positivity. Ten cases were Ki67 positive but Her2/neu negative while one case was Her2/neu positive but Ki67 negative. Conclusions: The present study demonstrated overexpression of Her2/neu and Ki67 in gallbladder cancer. A trend of decreasing Her2/neu expression with increasing grade of tumor was observed. Furthermore, greater Ki67 positivity was found in cases with lymph node metastasis and distant metastasis. Future studies with a larger number of patients will be required to precisely define the correlation of Her2/neu expression and Ki67 positivity with clinicopathological parameters. The results however are encouraging and suggest evaluation of Her2/neu as a candidate for targeted therapy.

• Tuberculosis and Respiratory Diseases
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• v.71 no.4
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• pp.259-265
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• 2011

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, are effective therapies for non-small cell lung cancer (NSCLC) patients whose tumors harbor somatic mutations in EGFR. The mutations are, however, only found in about 30% of Asian NSCLC patients and all patients ultimately develop resistance to these agents. Ionizing radiation has been shown to induce autophosphorylation of EGFR and activate its downstream signaling pathways. In the present study, we have tested whether the effect of gefitinib treatment can be enhanced after ionizing radiation. Methods: We compared the PC-9 and A549 cell line with its radiation-resistant derivatives after gefitinib treatment with cell proliferation and apoptosis assay. We also analyzed the effect of gefitinib after ionizing radiation in PC-9, A549, and NCI-H460 cells. Cell proliferation was determined by MTT assay and induction of apoptosis was evaluated by flow cytometry. Caspase 3 activation and PARP cleavage were evaluated by western blot analysis. Results: PC-9 cells having mutated EGFR and their radiation-resistant cells showed no significant difference in cell viability. However, radiation-resistant A549 cells were more sensitive to gefitinib than were their parental cells. This was attributable to an increased induction of apoptosis. Gefitinib-induced apoptosis increased significantly after radiation in cells with wild type EGFR including A549 and NCI-H460, but not in PC-9 cells with mutated EGFR. Caspase 3 activation and PARP cleavage accompanied these findings. Conclusion: The data suggest that gefitinib-induced apoptosis could increase after radiation in cells with wild type EGFR, but not in cells with mutated EGFR.

• BMB Reports
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• v.46 no.11
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• pp.527-532
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• 2013

Gangliosides are complex glycosphingolipids that are the major component of cytoplasmic cell membranes, and play a role in the control of biological processes. Human mesenchymal stem cells (hMSCs) have received considerable attention as alternative sources of adult stem cells because of their potential to differentiate into multiple cell lineages. In this study, we focus on various functional roles of gangliosides in the differentiation of hMSCs into osteoblasts or neuronal cells. A relationship between gangliosides and epidermal growth factor receptor (EGFR) activation during osteoblastic differentiation of hMSCs was observed, and the gangliosides may play a major role in the regulation of the differentiation. The roles of gangliosides in osteoblast differentiation are dependent on the origin of hMSCs. The reduction of ganglioside biosynthesis inhibited the neuronal differentiation of hMSCs during an early stage of the differentiation process, and the ganglioside expression can be used as a marker for the identification of neuronal differentiation from hMSCs.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1015-1018
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• 2016

Background: Overexpression or amplification of human epidermal growth factor receptor-2 (HER2) is associated with grade of malignancy and a poor prognosis in breast cancer (BC). The aim of this study was to evaluate of value of HER2 as a prognostic marker, and to analyze associations with common histopathological parameters in BC cases. Materials and Methods: Between of 2007 to 2014, 260 patients with BC referred to Oncology Clinic provided cancer tissue samples which underwent immunohistochemistry (IHC) for markers. ER and PR positivity was defined as ${\geq}10%$ positive tumor cells with nuclear staining. HER2-positive was defined as either HER2 gene amplification by fluorescent in situ hybridization (FISH) or scored as 3+ by IHC. For HER2 (2+), FISH was performed to determine HER2 positivity. Results: The mean age at diagnosis for the patients with HER2-negative was significantly higher than in HER2-positive cases. Also, there were significant correlations between histological grade, nuclear grade, lymph node metastasis, tumor size, ER status, PR status, p53 overexpression and Ki-67 index with HER2 expression. HER2-negative lesions were of higher grade and more likely to be ER-negative, PR-negative, p53-positive, lymph node metastasis, with a tumor size<2cm and also $Ki-67{\geq}20%$ as compared to the HER2-positive group. Conclusions: Contrary to the results of other studies, HER2-positive tumors in our study had a lower Ki-67 index and were p53-positive. Also, Ki-67 proliferation index ${\geq}20%$ in more studies was associated with p53-positive.Therefore, tumors which are HER2-positive and have a Ki-$67{\geq}20%$ had a more aggressive behavior compared to HER2-positive and Ki-67<20% lesions.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7597-7602
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• 2014

Background: Amplification and overexpression of human epidermal growth factor receptor 2 (HER2/neu) oncogene has considerable prognostic value in breast and gastric cancers. This study aimed to evaluate the frequency, overexpression pattern, clinical significance, and concordance between the results for protein expression and gene amplification of HER-2/neu in gastric and gastro-esophageal junction carcinomas. Materials and Methods: In this study, 101 gastric tissue samples which were included in tissue microarray were immunohistochemically examined for overexpression of HER2/neu. Chromogenic in situ hybridization (CISH) was used for HER-2/neu amplification. The correlation of HER2/neu amplification with clinicopathological parameters was also assessed. In addition, concordance between CISH and IHC was detected. Results: This study demonstrated a significant difference in the overexpression of HER2/neu in gastric tumors. The overexpression of HER2/neu was significantly higher in intestinal type, poorly differentiated grade, large size ($5cm{\leq}$) and positive nodal involvement tumors (p-value=0.041, 0.015, 0.038 and 0.071, respectively). Also, amplification of HER2/neu according to CISH test, had a significant positive correlation with tumor size and tumor type (p-value=0.018 and 0.058, respectively).Concordance between CISH and IHC was 76.9% in 101 evaluable samples. Conclusions: IHC/CISH differences were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumor heterogeneity in gastric cancers compared to breast cancers. Therefore, this can be a potential marker for targeted therapy of malignant gastric tumors.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7885-7889
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• 2014

Background: Activating mutations of epidermal growth factor receptor (EGFR) could predict response to tyrosine kinase inhibitor (TKI) treatment in patients with non-small cell lung cancer (NSCLC). However, the detection of EGFR mutation is frequently challenging in clinical practice for the lack of tumor tissue. The aim of this study was to investigate the feasibility of performing EGFR mutation testing on various types of liquid-based cytology (LBC) samples. Materials and Methods: A total of 434 liquid-based cytology samples were collected from March 2010 and November 2013. Among them, 101 with diagnosis of lung adenocarcinoma had paired surgically resected specimens. The ADx Amplification Refractory Mutation System (ADx-ARMS) was used to determine EGFR mutation status both in LBC and resected samples. Results: All liquid-based cytology samples were adequate for EGFR mutation analysis. The mutation rate was 50.5% in the 434 NSCLC patients with LBC samples and the incidence rates of EGFR mutation were consistent among different specimens. We also detected EGFR positives in 52.5% (53/101) patients with paired histologic specimens. The concordance rate of EGFR mutation between LBC samples and paired histologic specimens was 92.1%. Conclusions: Our results suggest that liquid-based cytology samples are highly reliable for EGFR mutation testing in patients with NSCLC.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4205-4208
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• 2016

Background: The aim of this study was to analyse the expression of EGFR in newly diagnosed and recurrent glioblastoma multiforme (GBM). Materials and Methods: Our study included a total of 48 paired samples collected from 24 patients diagnosed with GBM. The intensity of EGFR cytoplasmatic staining was scored on a scale of 1-3+ (weak, intermediate or strong). Results: We found EGFR overexpression in 23 patients (96%) with newly diagnosed GBM, while all recurrent tumours overexpressed EGFR. Ten recurrent tumours (42%) had a lower expression than their new counterpart 13 tumours (54%) had a similar expression, and only one case (2%) had increased expression on recurrence. The expression of EGFR in newly diagnosed GBM was significantly correlated with EGFR expression in recurrent tumour (p = 0.036). In addition, new GBMs with strong EGFR expression had a mean relapse-free interval of 11.5 months (p=0.017). A benefit of combined therapy was observed in the radiotherapy-plus-chemotherapy group where the average time was 11 months (p=0.011), as compared with surgery/radiotherapy alone (average time 6.8 months). Conclusions: The present data show that EGFR is overexpressed in paired GBMs. The discrepancies of EGFR expression between the primary tumour and the recurrence suggest heterogeneity of GBMs but also unity at relapse.