Functional invadopodia formation through stabilization of the PDPN transcript by IMP-3 and cancer-stromal crosstalk for PDPN expression.

We previously reported that insulin-like growth factor-II mRNA-binding protein-3 (IMP-3) depletion (IMP-3(Δ)) was shown to inhibit invadopodia formation and extracellular matrix degradation capacity in oral squamous cell carcinoma (OSCC) cells. In this study, we found that IMP-3(Δ) cells significantly downregulated the podoplanin (PDPN) level, which resulted in a loss of extracellular matrix degradation activity, although invadopodia was still thriving. From RNA in situ hybridization using a digoxigenin-labeled 3'UTR recognition probe of PDPN and reporter assay with 3'UTR of the PDPN gene cloned downstream from the luciferase reporter gene, we revealed that IMP-3 depletion was shown to be downregulated, which most probably lowered PDPN gene expression by reducing mRNA stabilization. In a xenograft model, PDPN depletion was the cause of a decrease in tumor volume and regional infiltration into nearby stroma. Taken together, transforming growth factor beta 1 increased PDPN expression, which potentiated cancer invasion through increased invadopodia formation and extracellular matrix degradation in the low invasive OSCC cell line. Reciprocally, interleukin-1 beta secreted by OSCC cells, stimulated transforming growth factor beta 1 secretion from stromal fibroblasts to induce PDPN expression in OSCC cells. In addition, a retrospective investigation of OSCC patients found that IMP-3 and PDPN expression significantly correlated with lymph node metastasis of OSCC patients. Moreover, co-expression of IMP-3 and PDPN were frequently detected both in primary and lymph nodes metastatic OSCC cells using immunohistochemical dual staining. Thus, the IMP-3-PDPN axis may be a sensitive target molecule in anti-invadopodia therapy for the treatment of metastatic cancers.

Clinicopathologic Review of Scalp Melanoma in Korea: A Single-Center Retrospective Study / 대한피부과학회지

Background@#Melanoma arising from the scalp is rare and often diagnosed at advanced stages due to difficulty in detection. @*Objective@#This is the first study that aimed to analyze the clinicopathological findings of scalp melanoma among Korean patients at a single institution. @*Methods@#In this single-centered retrospective study, medical records were used to review data of patients with scalp melanoma between 2006 to 2021. Chronic sun damage (CSD) was evaluated by reviewing histopathological findings of scalp melanoma. @*Results@#Fifteen patients were identified. Mean age at diagnosis was 53.93 years. In 14 cases, the tumors were located on hair-covered areas. Mean Breslow’s thickness was 6.06 mm. Nodular melanoma was the most common histologic type (n=9), followed by superficial spreading (n=5), and lentigo maligna (n=1). Ulceration was present in five cases. In nine cases, CSD was moderate. Elective neck node dissection was performed in 13 cases, with five revealing nodal involvement. At initial staging, three patients were in stage I, six were in stage II, four were in stage III, and two were in stage IV. Recurrence occurred in seven of the 15 cases. There were five confirmed mortalities during a mean follow-up period of 35 months. @*Conclusion@#In this study, the Breslow’s thickness of scalp melanoma was relatively deep, and the most frequent type was nodular melanoma. Since detection can be affected by black hair among Koreans, it may result in delayed diagnosis and poor prognosis. Therefore, more caution is needed when examining suspicious lesions on the scalp.

Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells

Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis. Traditional antiplatelet agents, such as aspirin, are thought to be potential chemotherapeutics, but they need to be used with caution because of the increased bleeding risk. Podoplanin (PDPN)-expressing cancer cells can activate platelets and promote OSCC metastasis. However, the reciprocal effect of platelets on PDPN expression in OSCC has not been investigated. In this study, we found that direct contact with platelets upregulated PDPN and integrin β1 at the protein level and promoted invasiveness of human OSCC Ca9.22 cells that express low levels of PDPN. In another human OSCC HSC3 cell line that express PDPN at an abundant level, silencing of the PDPN gene reduced cell invasiveness. Analysis of the public database further supported the co-expression of PDPN and integrin β1 and their increased expression in metastatic tissues compared to normal and tumor tissues of the oral cavity. Taken together, these data suggest that PDPN is a potential target to regulate platelet-tumor interaction and metastasis for OSCC treatment, which can overcome the limitations of traditional antiplatelet drugs.

Immunohistochemistry Biomarkers Predict Survival in Stage II/III Gastric Cancer Patients: From a Prospective Clinical Trial / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Identification of biomarkers to predict recurrence risk is essential to improve adjuvant treatment strategies in stage II/III gastric cancer patients. This study evaluated biomarkers for predicting survival after surgical resection. MATERIALS AND METHODS: This post-hoc analysis evaluated patients from the CLASSIC trial who underwent D2 gastrectomywith orwithout adjuvant chemotherapy (capecitabine plus oxaliplatin) at the Yonsei Cancer Center. Tumor expressions of thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and programmed death-ligand 1 (PD-L1) were evaluated by immunohistochemical (IHC) staining to determine their predictive values. RESULTS: Among 139 patients, IHC analysis revealed high tumor expression of TS (n=22, 15.8%), ERCC1 (n=23, 16.5%), and PD-L1 (n=42, 30.2%) in the subset of patients. Among all patients, high TS expression tended to predict poor disease-free survival (DFS; hazard ratio [HR], 1.80; p=0.053), whereas PD-L1 positivity was associated with favorable DFS (HR, 0.33; p=0.001) and overall survival (OS; HR, 0.38; p=0.009) in multivariate Cox analysis. In the subgroup analysis, poor DFS was independently predicted by high TS expression (HR, 2.51; p=0.022) in the adjuvant chemotherapy subgroup (n=66). High PD-L1 expression was associated with favorable DFS (HR, 0.25; p=0.011) and OS (HR, 0.22; p=0.015) only in the surgery-alone subgroup (n=73). The prognostic impact of high ERCC1 expression was not significant in the multivariate Cox analysis. CONCLUSION: This study shows that high TS expression is a predictive factor for worse outcomes on capecitabine plus oxaliplatin adjuvant chemotherapy, whereas PD-L1 expression is a favorable prognostic factor in locally advanced gastric cancer patients.

Ataxia-telangiectasia-mutated protein expression as a prognostic marker in adenoid cystic carcinoma of salivary glands / Шинэ санаа Шинэ нээлт

@#Adenoid cystic carcinoma (ACC) is one of the high grade malignant tumors in salivary glands, prognosticallycharacterized by multiple recurrences and late distant metastasis. Recently, Myb-NFIB fusion or rearrangements of Myb have been detected as a hallmark of ACC. However, no biological marker estimating the outcome of ACC has been proven yet. Purpose of this study was to investigate whether the protein expression of ATM gene is related to patients’ survival in ACC. This study consists of 48 surgical samples for detecting expression of ATM and its downstream p53. Kaplan-Meier plots were used to evaluate the relationship between the protein expression ratios of ATM, p53 and its ATM-mediated phosphorylation and the overall survival rate of patients with ACC. low expression of ATM in cancer cells correlated with poor survival rate (p = 0.037). However, low expression of ATM in stromal fibroblasts was not significantly associated with patient outcome. Moreover, this study evaluated ATM expression stratified by p53 and its ATM-mediated phosphorylation status. ATM loss was associated with a significantly decreased overall survival in patients simultaneously showing overexprssion of p53 (p = 0.01) and low expression of p53 phospho S15 (p = 0.05). These data supported that loss of ATM and its functional status in p53 pathway is an important factor associated with poor outcome of patients in ACC of salivary glands.

Ataxia-Telangiectasia-Mutated Protein Expression as a Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

PURPOSE: Adenoid cystic carcinoma (ACC) is a high-grade malignant tumor of the salivary glands, clinically characterized by multiple recurrences and late distant metastasis. Biological markers for assessing the prognosis of ACC have remained elusive. The purpose of this study was to investigate whether the protein expressions of ataxia telangiectasia mutated (ATM), p53, and ATM-mediated phosphorylated p53 are related to patient survival in ACC. MATERIALS AND METHODS: In this study, 48 surgical samples were used to assess the expressions of ATM and its downstream target p53. Fisher's exact test and Kaplan-Meier analysis were conducted to evaluate the role of ATM, p53, and phospho-p53 (S15) protein expressions in predicting patient survival and distant metastasis. RESULTS: Myb expression was positive in 85.4% of ACCs, but did not reflect patient survival rate. In contrast, low expression of ATM in cancer cells was significantly correlated with poor survival rate (p=0.037). Moreover, under positive p53 expression, low expression of ATM was highly predictive of poor survival in ACC (p=0.017). CONCLUSION: These data indicate that combined assessment of ATM and p53 expression can serve as a useful prognostic marker for assessing survival rate in patients with ACC of the salivary glands.

Use of a Combined Gene Expression Profile in Implementing a Drug Sensitivity Predictive Model for Breast Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Chemotherapy targets all rapidly growing cells, not only cancer cells, and thus is often associated with unpleasant side effects. Therefore, examination of the chemosensitivity based on genotypes is needed in order to reduce the side effects. MATERIALS AND METHODS: Various computational approaches have been proposed for predicting chemosensitivity based on gene expression profiles. A linear regression model can be used to predict the response of cancer cells to chemotherapeutic drugs, based on genomic features of the cells, and appropriate sample size for this method depends on the number of predictors. We used principal component analysis and identified a combined gene expression profile to reduce the number of predictors. RESULTS: The coefficients of determinanation (R²) of prediction models with combined gene expression and several independent gene expressions were similar. Corresponding F values, which represent model significances were improved by use of a combined gene expression profile, indicating that the use of a combined gene expression profile is helpful in predicting drug sensitivity. Even better, a prediction model can be used even with small samples because of the reduced number of predictors. CONCLUSION: Combined gene expression analysis is expected to contribute to more personalized management of breast cancer cases by enabling more effective targeting of existing therapies. This procedure for identifying a cell-type-specific gene expression profile can be extended to other chemotherapeutic treatments and many other heterogeneous cancer types.

Analysis of patients with ovarian cancer recurrence after treatment of lymph node regions alone and prognosis of survival / 中国基层医药

Objective To explore effects,survival and prognostic factors of regional lymph node recurrence of ovarian cancer patients after surgery in our hospital.Methods 1 348 cases of ovarian cancer in our hospital,regional lymph nodes filter out the postoperative recurrence alone were selected,44 cases were analyzed through a complete medical history,then the recurrence characteristics,treatment,prognosis,and prognostic factors were obtained.Results According to the disease,44 patients were treated with the second surgery,radiotherapy or chemotherapy,completed remission after treatment in 36 cases,some improvement in 7 cases,1 case,no significant improvement.44 patients 5-year cumulative survival rate was 65.32％,lymph node dissection adjuvant chemotherapy group,local radiotherapy and chemotherapy group,chemotherapy group cumulative survival difference were statistically significant (Kaplan-Meierx2 =23.685,P =0.000);may affect prognostic factors univariate Log-rank analysis showed that age,the recurrence time,the number of tumor recurrence and prognosis (x2 =11.254,9.254,15.625,all P ＜ 0.05) ; Cox regression analysis showed that age,time to recurrence,relapse foci were independent prognostic factors (P =0.000,0.006,0.000).Conclusion The patients with ovarian cancer recurrence after surgery alone has its unique regional lymph node characteristics,treatment should consider the factors affecting the prognosis.

nm23-H1 Protein Expression and Gene Mutation in 150 Patients with Non-Hodgkin's Lymphomas

The metastasis-suppressing role of the nm23 gene in the metastatic spread of malignant tumor is still debated. We examined the nm23-H1 protein expression and gene mutation in non-Hodgkin's lymphomas to compare with the clinicopathologic parameters. The expression of nm23-H1 protein was immunohistochemically examined in 150 cases of non-Hodgkin's lymphomas; 85 diffuse large B cell lymphomas (DL-BCL), 18 marginal zone B cell lymphomas (MZL), 3 mantle cell lymphomas, 25 peripheral T cell lymphomas, not otherwise specified (TCLNOS), and 19 NK/T cell lymphomas (NK/T). Eighty-one cases (58 DLBCL, 6 MZL, 4 TCLNOS, and 13 NK/T) were studied for nm23-H1 gene mutation in exon 1 to 5. The high expression of nm23-H1 protein was associated with the high IPI score (p=0.019) and the low survival rate of the patients (p=0.0039). The gene mutation of nm23-H1 was detected in 10.3% of DLBCL and 30.7% of NK/T; but none in MZL and TCLNOS. The mutation was found in exon 1 in 5 cases, exon 2 in two cases, exon 4 in one case and both exon 1 and 2 in two cases. Our results suggest that the expression of nm23-H1 protein can be used as a poor prognostic marker in non-Hodgkin's lymphomas, and the mutational change of gene may operate in the lymphomagenesis.

Expression of p63,bcl-2,bcl-6 and p16 in Basal Cell Carcinoma and Squamous Cell Carcinoma of the Skin

BACKGROUND: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the common malignant neoplasms of the skin. The p63 is a p53 homologue which is considered to be a reliable keratinocyte stem cell marker. Bcl-2 plays a key role in cell longevity by preventing apoptosis, whereas the bcl-6 gene functions as a transcriptional repressor. The p16-CDK4/6 complex arrests the cell cycle at G0 /G1 phase. In the present study, the expression of p63, bcl-2, bcl-6, and p16 in BCC and SCC was evaluated. METHODS: Forty-seven BCCs and 43 SCCs were selected and microarrayed in paraffin blocks. Immunohistochemical analysis was performed with specific antibodies for bcl-2, bcl-6, p16 and p63. RESULTS: p63 was found to be expressed in all BCCs and SCCs. Bcl-2 was exclusively expressed in BCCs (100%), but there was negative expression in SCCs, whereas bcl-6 was positively expressed in 18.2% of SCCs, and was negative in BCCs. In SCCs, p16 was expressed at high frequency (47.7%) than in BCCs (14.9%). The expression of p16 was correlated with the histologic grades of SCCs. CONCLUSION: The different patterns of bcl-2, bcl-6, p63 and p16 protein expression between BCCs and SCCs may represent the different histogenesis and morphologic features of two lesions.

Pax5 expression in Non-Hodgkin's Lymphomas and Acute Leukemias

The Pax5 gene encodes the B-cell-specific activator protein which is a key regulator in development and differentiation of B-cell. We studied the expression of Pax5 in hematologic malignancies to evaluate the diagnostic utility as a B cell marker. Materials included 70 B cell lymphomas, 26 T cell lymphomas, 53 acute leukemias, and 6 multiple myelomas (MMs). Representative areas from the paraffinembedded tissues were selected for tissue microarray, and the expressions of Pax5 was immunohistochemically evaluated. Pax5 was strongly expressed in most of the B cell lymphomas; 44 of 47 diffuse large B cell lymphomas (93.6%), 15 of 16 marginal zone B cell lymphomas (93.8%), all 3 mantle cell lymphomas, 2 follicular lymphomas, and 2 Burkitt's lymphomas (100%). However, Pax5 was expressed in only one of 26 T cell lymphomas. Among leukemias, it was expressed in 10 of the 14 B acute lymphocytic leukemias (ALLs) (72.4%), but also in 3 of the 6 T ALLs (50%), 13 of the 26 acute myelogenous leukemias (AMLs) (50%) and in all 3 ALL arising in chronic myelogenous leukemias and 4 mixed B ALL and AML. In MMs, Pax5 was negative in all cases. We concluded that Pax5 is very useful B cell marker in classification of lymphomas, but not of acute leukemias.

cDNA Microarray Expression Analysis in HPV-Infected Uterine Cervical Cancer Cell Line / 대한산부인과학회잡지

OBJECTIVE: To estimate the difference in gene expression related to carcinogenesis between HPV 16 positive squamous cell carcinoma and HPV 16 positive adenocarcinoma of cervix. METHODS: We used cDNA microarray technology to identify alterations in gene expression of human cervical cancers. Gene expression of three cell lines, CaSki and SiHa (HPV 16 positive squamous cell carcinoma) and HeLa (HPV 16 positive adenocarcinoma) were compared with HT3 (HPV 16 negative squamous cell carcinoma). The microarray contains twin spots for 344 cancer-associated genes. RESULTS: The analysis showed several interesting findings: (1) In all three squamous cell lines, CD4, CSF1, MMP15 and TNFR6 were increased, whereas SLC3A2 were decreased, (2) Only in adenocarcinoma cell line HeLa, CDC25A, CDK2, CDK9, IL2, PF4, MAD, FCER2, MAP4K1 and MS4A1 were increased, and PLAU, IL8, IL9R and ATK were decreased. (3) In both squamous cell carcinoma cell lines CaSki and SiHa, 61 genes which belong to chemokine, cell cycle, growth factor, interleukin, adhesion molecule, protein kinase and TNF were increased, whereas 10 genes which are associated with apoptosis and cytokine were increased only in SiHa, and 97 genes which are associated with a variety of cell functions were increased only in CaSki. CONCLUSION: We suggest that there might be common, but also different carcinogenic mechanisms involved in HPV 16 related cervical cancers according to the histologic subtypes and different tumors.