FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

Influences of Tobacco-Related Knowledge on Awareness and Behavior towards Smoking

BACKGROUND: A considerable amount of research has shown that knowledge and appropriate awareness are essential for encouraging positive behaviors and promoting health. In Korea, the roles that behavioral changes play in the prevention of cancer have been an important issue since the introduction of the 10 codes for cancer prevention in 2006. Thus, the present study investigated the associations of tobacco-related knowledge with awareness and attitudes towards positive smoking-cessation behaviors. METHODS: The present study analyzed data from the 2010 national questionnaire survey (n = 1,006). This study evaluated sociodemographic characteristics, smoking status, self-rated health status, health-related interests, and the accuracy of 12 tobacco-related statements to determine knowledge level and to investigate its impact on awareness and behaviors related to smoking. These parameters were examined and staged using the Precaution Adoption Process Model. RESULTS: A higher level of tobacco-related knowledge was significantly associated with a positive attitude towards smoking cessation (5–8 correct answers: odds ratio [OR], 2.53; 95% confidence interval [CI], 1.57–4.08; ≥ 9 correct answers: OR, 3.90; 95% CI, 2.22–6.82; reference: ≤ 4 correct answers). Interestingly, among current smokers, only those who correctly responded to ≥ 9 of 12 tobacco-related statements were significantly associated with a positive attitude towards smoking cessation. CONCLUSION: This study found that having a higher level of tobacco-related knowledge had a significant impact on positive attitudes towards smoking cessation. This suggests that there is a need to disseminate appropriate knowledge to the general population to encourage positive attitudes and promote healthful behaviors in terms of smoking.

Feasibility of Polycaprolactone Scaffolds Fabricated by Three-Dimensional Printing for Tissue Engineering of Tunica Albuginea

PURPOSE: To investigate the feasibility of a polycaprolactone (PCL) scaffold fabricated by three-dimensional (3D) printing for tissue engineering applications for tunica albuginea. MATERIALS AND METHODS: PCL scaffolds were fabricated by use of a 3D printing system. Two scaffolds were fabricated that differed in the architecture of the lay-down pattern: a 90°PCL scaffold and a 45°PCL scaffold. Mechanical properties were measured to compare tensile strength between the two scaffold types. The scaffolds were characterized by scanning electron microscope (SEM) images. The scaffolds were seeded with fibroblast cells, and the ability of these scaffolds to support the cells was evaluated by immunofluorescence staining. RESULTS: The PCL scaffolds had well-structured shapes, regular arrays, and good interconnection in SEM images. The horizontal and vertical Young's modulus coefficients were 13 and 12 MPa for the 90°PCL scaffold and 19 and 21 MPa for the 45°PCL scaffold, respectively. Microscopy images revealed that human fibroblast cells covered the entire scaffold surface. Immunofluorescence staining of ER-TR7 confirmed that the fibroblast cells remained viable and proliferated throughout the time course of the culture. CONCLUSIONS: This preliminary study provides experimental evidence for the feasibility of 3D printing of PCL scaffolds for tissue engineering applications of tunica albuginea.

Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1 / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. MATERIALS AND METHODS: Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. RESULTS: In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1alpha (HIF-1alpha) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1alpha activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. CONCLUSION: Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1alpha-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.

Stomach cancer incidence rates among Americans, Asian Americans and Native Asians from 1988 to 2011 / 한국역학회지

Stomach cancer is the second most common cancer in Eastern Asia, accounting for approximately 50% of all new cases of stomach cancer worldwide. Our objective was to compare the stomach cancer incidence rates of Asian Americans in Los Angeles with those of native Asians to assess the etiology of stomach cancer from 1988 to 2011. To examine these differences, Asian Americans (Korean, Japanese, Chinese, and Filipino Americans living in Los Angeles, California, USA) and native Asians (from Korea, Japan, China, and the Philippines) were selected for this study. Using the Cancer Incidence in Five Continents database, stomach cancer incidence rates were examined. Data from the National Cancer Registry of Korea were used for native Koreans. Between native countries, the incidence rates in Japan, China, the Philippines, and the US declined over time, but the incidence in Korea has remained constant. The incidences among Asian immigrants were lower than those among native Asians. The incidence rates of males were approximately 2 times higher than those among females in Asian countries were. The effect of immigration on stomach cancer incidence suggests that lifestyle factors are a significant determinant of stomach cancer risk. However, the incidence in Korea remains the highest of these countries.