• Molecules and Cells
• /
• v.44 no.1
• /
• pp.50-62
• /
• 2021

Among all cancer types, lung cancer ranks highest worldwide in terms of both incidence and mortality. The crosstalk between lung cancer cells and their tumor microenvironment (TME) has begun to emerge as the "Achilles heel" of the disease and thus constitutes an attractive target for anticancer therapy. We previously revealed that crosstalk between lung cancer cells and endothelial cells (ECs) induces chemoresistance in multicellular tumor spheroids (MCTSs). In this study, we demonstrated that factors secreted in response to crosstalk between ECs and lung cancer cells play pivotal roles in the development of chemoresistance in lung cancer spheroids. We subsequently determined that the expression of hypoxia up-regulated protein 1 (HYOU1) in lung cancer spheroids was increased by factors secreted in response to crosstalk between ECs and lung cancer cells. Direct interaction between lung cancer cells and ECs also caused an elevation in the expression of HYOU1 in MCTSs. Inhibition of HYOU1 expression not only suppressed stemness and malignancy, but also facilitated apoptosis and chemosensitivity in lung cancer MCTSs. Inhibition of HYOU1 expression also significantly increased the expression of interferon signaling components in lung cancer cells. Moreover, the activation of the PI3K/AKT/mTOR pathway was involved in the HYOU1-induced aggression of lung cancer cells. Taken together, our results identify HYOU1, which is induced in response to crosstalk between ECs and lung cancer cells within the TME, as a potential therapeutic target for combating the aggressive behavior of cancer cells.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.9
• /
• pp.4079-4083
• /
• 2014

Background: Previous studies have showed that argonaute 2 is a potential factor related to genesis of several cancers, however, there have been no reports concerning gliomas. Methods: Paraffin specimens of 129 brain glioma cases were collected from a hospital affiliated to Binzhou Medical University from January 2008 to July 2013. We examined both argonaute 2 mRNA and protein expression by real-time quantitative PCR (qRT-PCR), Western blot analysis, and immunohistochemistry (IHC). The survival curves of the patients were determined using the Kaplan-Meier method and Cox regression, and the log-rank test was used for statistical evaluations. Results: Both argonaute 2 mRNA and protein were upregulated in high-grade when compared to low-grade tumor tissues. Multivariate analysis revealed that argonaute 2 protein expression was independently associated with the overall survival (HR=4.587, 95% CI: 3.001-6.993; P=0.002), and that argonaute 2 protein expression and WHO grading were independent prognostic factors for progression-free survival (HR=4.792, 95% CI: 3.993-5.672; P<0.001, and HR=2.109, 95% CI: 1.278-8.229; P=0.039, respectively). Kaplan-Meier analysis with the log-rank test indicated that high argonaute 2 protein expression had a significant impact on overall survival (P=0.0169) and progression-free survival (P=0.0324). Conclusions: The present study showed that argonaute 2 expression is up-regulated in gliomas. Argonaute 2 might also serve as a novel prognostic marker.

• Molecular & Cellular Toxicology
• /
• v.1 no.1
• /
• pp.62-71
• /
• 2005

For toxicity model in the kidney, renal cell carcinoma (RCC) is one of the most important model to assess the structural and functional alterations. Most RCCs are sporadic, and environmental agents are suspected to play a role in the etiology of the disease. In this study, we discovered novel evidence for previously unknown gene expression patterns related to progression according to cancer stage in RCC. Four clear cell RCC tissue samples along with five corresponding patient-matched normal kidney tissue samples were obtained from patients undergoing partial or radical nephrectomy. To examine the difference of gene expression profile in clear cell RCC, radioactive cDNA microarrays were used to evaluate changes in the expression of 1,152 genes in a total. Using $^{33}P-labeled$ probes, this method provided highly sensitive gene expression profiles including drug metabolism, and cellular signaling. 29 genes were identified with expression levels that differed by more than 2.0 value of z-ratio, compared with that in control. Whereas expression of 38 genes were decreased by less than-2.0 value of z-ratio. In conclusion, this study has identified 67 gene expression alterations in clear-cell type of RCC. Most notably, genes involved in cell growth were up-regulated in stage I more than stage III whereas genes involved in signal transduction were down-regulated in which both stage I and stage III. The identified alteraions of gene expression will likely give in sight in to clear cell RCC and tumor progression.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.2
• /
• pp.771-774
• /
• 2016

Thymic tumors are the most common tumors in the anterior mediastinum. Total resection is the main treatment and predictor of longer survival. Adjuvant radiotherapy alone or in combination with chemotherapy is recommended with incomplete excision or advanced disease. Thirty seven patients with thymic tumors were included in this retrospective study from January 2001 till December 2012. They were studied regarding age, sex, performance status, tumor size and invasion, stage, pathology, treatment given, overall and progression free survival. Myasthenia gravis was present in 18.1% of the patients. Masaoka stage III was diagnosed in 40.5% of the cases followed by stage II in 24.3% and the other stages with lower percentages. Pathology type B3 was the most frequent followed by B2 and B1 with percentages of 27, 24.3 and 21.7 respectively. Complete resection was conducted in 11 cases (29.75%). Partial resection or debulking was done in 15 (40.5%) and a biopsy was taken in 11 cases (29.8%) Adjuvant chemotherapy was given to 14 patients (37.8%) and neoadjuvant to 13 (35.2%). Adjuvant radiotherapy was given to 17 patients (46%) and neoadjuvant to 14 (37.8%). The 5-year overall survival by was 83% for stage I, 71% for stage II, 60% for stage III, and 44% for stage IV (p=0.0426). Five year progression free survival was 71% for stage I, 62% stage II, 42% stage III, and 37% for stage IV (p=0.0532). In conclusion with the rare thymic tumors early stage and complete resection have the highest impact on overall and progression free survival.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.1
• /
• pp.245-252
• /
• 2014

Human METCAM/MUC18, a cell adhesion molecule (CAM) in the immunoglobulin-like gene super family, plays a dual role in the progression of several epithelium cancers; however, its role in the nasopharyngeal carcinoma (NPC) remains unclear. To initiate the study we determined human METCAM/MUC18 expression in tissue samples of normal nasopharynx (NP), NPCs, and metastatic lesions, and in two established NPC cell lines. Immunoblotting analysis was used for the determination in lysates of frozen tissues, and immunohistochemistry (IHC) for expression in formalin-fixed, paraffin-embedded tissue sections of 7 normal nasopharynx specimens, 94 NPC tissue specimens, and 3 metastatic lesions. Human METCAM/MUC18 was expressed in 100% of the normal NP, not expressed in 73% of NPC specimens (or expressed at very low levels in only about 27% of NPC specimens), and expressed again in all of the metastatic lesions. The level of human METCAM/MUC18 expression in NPC tissues was about one fifth of that in the normal NP and metastatic lesions. The low level of human METCAM/MUC18 expression in NPC specimens was confirmed by a weak signal of RT-PCR amplification of the mRNA. Low expression levels of human METCAM/MUC18 in NPC tissues were also reflected in the seven established NPC cell lines. These findings provided the first evidence that diminished expression of human METCAM/MUC18 is an indicator for the emergence of NPC, but increased expression then occurs with metastatic progression, suggesting that huMETCAM/MUC18, perhaps similar to TGF-${\beta}$, may be a tumor suppressor, but a metastasis promoter for NPC.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.12
• /
• pp.5025-5030
• /
• 2015

Immunoregulatory cytokines have an influence on hepatitis C virus (HCV) infection outcome. This study aimed to determine whether single nucleotide polymorphisms (SNP) in IFN- ${\gamma}$ and IL-10 genes are associated with susceptibility and/or are markers of prognosis regarding chronic hepatitis C outcomes. IFN ${\gamma}$ (+874T/A) and IL-10 (-1082G/A) genotypes were determined in 75 HCV genotype 4 patients with different disease severities (chronic hepatitis, n=25, liver cirrhosis and hepatocellular carcinoma (HCC) on top of liver cirrhosis, n=50) and 25 healthy participants using allele-specific polymerase chain reaction. No statistical differences in allele or genotype distributions of IFN ${\gamma}$ and IL-10 genes were detected between patients and controls or between patientgroups. No significant difference in the frequency of IL-10 SNP at position -1082 or IFN-${\gamma}$ at position +874T/A was found between chronic HCV genotype 4 and with progression of disease severity in liver cirrhosis or HCC. In conclusion; interferon-${\gamma}$ and interleukin-10 gene polymorphisms are not predictors of disease progression in patients with chronic hepatitis C (Genotype-4).

• Asian Pacific Journal of Cancer Prevention
• /
• v.13 no.7
• /
• pp.3437-3441
• /
• 2012

Background: Oncogenic Bmi-1 (B-lymphoma Moloney murine leukemia virus insertion region-1) belongs to the Polycomb-group (PcG) family of proteins and plays an important role in the regulation of proliferation, senescence, cell cycle and apoptosis, chromosome stability, activation of gene transcription. Methods: To clarify the roles of Bmi-1 in tumourigenesis and progression of gastric carcinomas, it was examined by immunohistochemistry (IHC) and real-time RT-PCR in gastric carcinomas, dysplasia, intestinal metaplasia (IM), and gastritis with a comparison of its expression with clinicopathological parameters of carcinomas. Results: There was gradually increased Bmi-1 protein expression from gastritis, IM, dyplasia to carcinoma (p<0.001). Bmi-1 expression was positively linked to tumor size, depth of invasion, lymph node metastasis and worse prognosis of carcinomas (p<0.001), but not to age or sex of carcinoma patients (p>0.05). There was higher Bmi-1 protein expression in intestinal-type carcinomas than diffuse-type ones (p<0.001). At mRNA level, Bmi-1 protein expression was increased from gastritis, IM, dysplasia and carcinoma (p<0.001). Bmi-1 overexpression was observed in gastric carcinoma with larger diameter, deeper invasion, lymph node metastasis, and intestinal-type carcinoma (p<0.05). Conclusion: These findings indicate that up-regulated Bmi-1 expression is positively linked to pathogenesis, growth, invasion, metastasis and differentiation of gastric carcinomas. It was considered as a promising marker to indicate the aggressive behaviors and prognosis of gastric carcinomas.

• BMB Reports
• /
• v.48 no.7
• /
• pp.413-418
• /
• 2015

DEPDC1 is a recently identified novel tumor-related gene that is upregulated in several types of cancer and contributes to tumorigenesis. In this study, we have investigated the expression pattern and functional implications of DEPDC1 during cell cycle progression. Expression studies using synchronized cells demonstrated that DEPDC1 is highly expressed in the mitotic phase of the cell cycle. Immunofluorescence assays showed that DEPDC1 is predominantly localized in the nucleus during interphase and is redistributed into the whole cell upon nuclear membrane breakdown in metaphase. Subsequently, siRNA-mediated knockdown of DEPDC1 caused a significant mitotic arrest. Moreover, knockdown of DEPDC1 resulted in remarkable mitotic defects such as abnormal multiple nuclei and multipolar spindle structures accompanied by the upregulation of the A20 gene as well as several cell cycle-related genes such as CCNB1 and CCNB2. Taken together, our current observations strongly suggest that this novel cancerous gene, DEPDC1, plays a pivotal role in the regulation of proper mitotic progression. [BMB Reports 2015; 48(7): 413-418]

• Experimental and Molecular Medicine
• /
• v.50 no.11
• /
• pp.10.1-10.11
• /
• 2018

Although early studies suggested that bladder cancer (BCa) is more prevalent in men than in women, muscle-invasive rates are higher in women than in men, suggesting that sex hormones might play important roles in different stages of BCa progression. In this work, we found that estrogen receptor beta ($ER{\beta}$) could increase BCa cell proliferation and invasion via alteration of miR-92a-mediated DAB2IP (DOC-2/DAB2 interacting protein) signals and that blocking miR-92a expression with an inhibitor could partially reverse $ER{\beta}$-enhanced BCa cell growth and invasion. Further mechanism dissection found that $ER{\beta}$ could increase miR-92a expression at the transcriptional level via binding to the estrogen-response-element (ERE) on the 5' promoter region of its host gene C13orf25. The $ER{\beta}$ up-regulated miR-92a could decrease DAB2IP tumor suppressor expression via binding to the miR-92a binding site located on the DAB2IP 3' UTR. Preclinical studies using an in vivo mouse model also confirmed that targeting this newly identified $ER{\beta}$/miR-92a/DAB2IP signal pathway with small molecules could suppress BCa progression. Together, these results might aid in the development of new therapies via targeting of this $ER{\beta}$-mediated signal pathway to better suppress BCa progression.

• Korean Journal of Head & Neck Oncology
• /
• v.38 no.2
• /
• pp.7-13
• /
• 2022

Human papillomavirus (HPV) is a causative agent for a subset of oropharyngeal cancer (OPC). The current standard of care (SOC) for locally advanced OPC is 70 Gy definitive radiotherapy (RT) concurrent with cisplatin, which entails significant proportions of acute and late grade 3 or higher toxicities. Accordingly, discovery of favorable prognosis of HPV-related OPC has led to enthusiasm to attenuate subspecialties therapy in multidisciplinary treatment. Diverse deintensification strategies were investigated in multiple phase 2 trials with an assumption that attenuated treatments result in comparable oncologic outcome and less toxicities compared with SOC. Several trials on chemotherapy deintensification revealed that concomitant administration of cisplatin is not to be omitted or substituted for cetuximab without compromising progression-free survival or local control. A transoral robotic surgery (TORS) is investigated as alternative local treatment, but TORS plus SOC or mild deintensified adjuvant RT showed similar toxicities and inferior oncologic outcomes compared with SOC definitive RT or moderately deintensified RT. However, it has been reported that TORS plus deintensified 30-36 Gy adjuvant RT results in excellent outcome and less late toxicity compared with SOC adjuvant RT. Several phase 2 trials reported apparently equivalent progression-free survival and local control and similar adverse effects with moderately deintensified 60 Gy RT compared with SOC 70 Gy RT. Further dose reduction below 60 Gy has been investigated using biology-directed approaches, which use response to induction chemotherapy or metabolic images to triage HPV-positive OPC for deintensified RT. In summary, these trials provide valuable insights for future directions. Available evidence consistently showed that moderately deintensified RT is effective and safe for HPV-positive OPC in both definitive and adjuvant settings. Concurrent cisplatin remains an essential component without which progression-free survival is significantly compromised for advanced HPV-positive OPC. A simple incorporation of TORS to SOC may be detrimental for oncologic outcome without anticipated toxicity reduction. Given the lack of level 1 evidence, it is prudent to curb an unjustified deviation from the current SOC and limit any deintensified strategies to clinical trials and adhere to the current SOC.