Juhie Lee

Balance between SIRT1 and DBC1 expression is lost in breast cancer

SIRT1 (silent mating‐type information regulation 2 homologue 1)‐mediated cellular resistance to various stresses is negatively regulated by deleted in breast cancer 1 (DBC1), which was originally reported to be deleted in breast cancer. However, the suggested functions of SIRT1 as a potential tumor promoter and of DBC1 as a potential tumor suppressor have been challenged by observations of their respective down‐ and up‐regulation in various cancers. The aim of the present study was to simultaneously evaluate the expression levels of SIRT1 and DBC1 in the normal and tumor breast tissues from 28 breast cancer patients and to determine correlations with clinicopathological variables. SIRT1 and DBC1 expression was higher in tumor tissues than in matched normal tissues at the protein level, but not at the transcriptional level. Overexpression of SIRT1 and DBC1 in tumor tissue was correlated with favorable and unfavorable clinicopathological factors, suggesting their pleiotropic functions as a potential tumor promoter and tumor suppressor in tumorigenesis. Interestingly, although the overall expression of SIRT1 and DBC1 increased in tumor breast tissues, the correlation between SIRT1 and DBC1 expression was weaker in tumor tissue than in normal tissue. This suggests that the negative regulation of SIRT1 by DBC1 may retard tumorigenesis in breast tissue. Therefore, the correlation between SIRT1 and DBC1 is a potential prognostic indicator in breast cancer. (Cancer Sci 2010)

Comparison of adjuvant chemotherapy and radiation in patients with intermediate risk factors after radical surgery in FIGO stage IB–IIA cervical cancer

The aim of this study was to compare the outcome of chemotherapy or radiation as adjuvant therapy for patients with FIGO stage IB–IIA cervical cancer and surgically confirmed intermediate risk factors. Data were collected from patients with uterine cervical cancer FIGO stage IB–IIA who had adjuvant chemotherapy following radical hysterectomy with pelvic lymph node dissection (RHLND, cases) or adjuvant radiotherapy following RHLND (controls). The study groups consisted of 38 cases and 42 controls. Adjuvant treatment was given to the patients with a combination of intermediate risk factors including deep stromal invasion (>50%), lymphvascular space invasion, large tumor size (3–6 cm), or close vaginal resection margin (<1 cm). Comparison of the cases with the controls revealed no significant differences in variables studied including median age (P= 0.18), stage distribution (P= 0.30), histologic subtype (P= 0.93), pathologic tumor size (P= 0.46), depth of the stromal invasion (P= 0.29), lymphvascular space invasion (P= 0.50), and close vaginal resection margin (P= 0.62). The difference in disease-free survival rates was not significant (P= 0.68). However, the overall survival analysis was incomplete due to the limited number of events available at the end of the study period. The findings of this study suggest that adjuvant chemotherapy in patients with FIGO stage IB–IIA uterine cervical cancer and surgically confirmed intermediate risk factors may be effective.

TGF-β1 inhibition of apoptosis through the transcriptional up-regulation of Bcl-X L in human monocytic leukemia U937 cells

To characterize the TGF-β1 response of monocytic leukemia cells, we analyzed the effects of TGF-β1 on cell proliferation, differentiation, and apoptosis of human monoblastic U937 cells. Treatment of cells with TGF-β1 in the absence of growth factors significantly enhanced cell viability. Flow cytometric analysis of DNA content and CD14 expression revealed that TGF-β1 does not affect cell proliferation and differentiation. Consistent with these results was the finding that no transcriptional induction of Cdk inhibitors such as p21Waf1, p15Ink4b, and p27Kip1 was detected following TGF-β1 treatment. Interestingly, however, pretreatment of TGF-β1 significantly inhibited Fas-, DNA damage-, and growth factor deprivation-induced apoptosis. This antiapoptotic effect was totally abrogated by anti-TGF-β1 antibody. Quantitative RT-PCR analysis demonstrated a dose- and time-dependent transcriptional up-regulation of Bcl-X(L), suggesting its implication in the TGF-1-mediated antiapoptotic pathway. We also observed elevated expression of c-Fos and PTEN/MMAC1. But, no detectable change was recognized in expression of c-Jun, Fas, Fadd, Fap-1, Bcl-2, and Bax. Taken together, our study shows that TGF-β1 enhancement of cellular viability is associated with its antiapoptotic effect, which may result from the transcriptional up-regulation of Bcl-X(L).

Polarized CD163+ tumor-associated macrophages are associated with increased angiogenesis and CXCL12 expression in gastric cancer.

PURPOSEnTumor-associated macrophages (TAMs) play a significant role in tumor progression and angiogenesis. However, the prognostic value of TAMs in different histologic locations of gastric cancer (GC) is still unknown. We evaluated the distribution of TAMs in different histologic locations to investigate its importance in predicting prognosis and the relationship with angiogenesis and CXCL12 expression in GC.nnnMETHODS AND MATERIALSnThe distribution of TAMs and microvessel density (MVD) in 113 GC samples were evaluated by immunohistochemical staining of CD163 and CD105, respectively. The extent of TAM distribution in the tumor was categorized into three groups: infiltrated TAMs in the tumor nest (TN), tumor stroma (TS) and invasive tumor margin (TM). The expression of CXCL12 in GC were evaluated by immunohistochemical staining of tissues from 88 GC samples.nnnRESULTSnThe increased CD163+ TAMs in TS and TM were closely correlated with tumor size, depth of invasion, TNM stage, lymph node metastasis, and lymphovascular invasion. TAMs in TN was not related with any clinicopathologic characteristics except histologic differentiation. The high infiltration of CD163+ TAMs in TS and TM were significantly correlated with poor overall survival. Regardless of location, CD163+ TAMs were significantly correlated with increased MVD. CXCL12 expression was significantly associated with increased CD163+ TAMs in TS and TM.nnnCONCLUSIONSnTAMs in different histologic locations in GC were related to distinct aspects of tumor progression. CD163+ TAMs in TS and TM are associated with tumor progression and CXCL12 expression in GC. TAMs may be involved in tumor progression through the angiogenesis.

Expression of BDNF, TrkB, and p53 in early-stage squamous cell carcinoma of the uterine cervix.

Aims: TrkB and BDNF play a critical role in cancer invasion and metastasis. We investigated the potential role of these proteins, together with p53, in squamous cell carcinoma (SCC) of the uterine cervix by focusing on the clinicopathological correlation and outcome. Methods: We performed RT-PCR analysis of TrkB and BDNF mRNA expression in cervical cancer cell lines, as well as tumour and normal tissue of the cervix. We analysed TrkB, BDNF, and p53 protein expression using immunohistochemistry in 80 patients with cervical SCC. Results: The expression of BDNF and TrkB mRNA was higher in human cervical cancer cell lines and SCC tissues than in normal tissues. Positive TrkB expression was significantly correlated with low FIGO stage (pu200a=u200a0.032), low T stage (pu200a=u200a0.027), less than 1/2 stromal invasion of the cervix (pu200a=u200a0.018), 4u200acm or smaller for the greatest dimension of the tumour (pu200a=u200a0.015) and absent lymphatic invasion (pu200a=u200a0.032). Positive BDNF expression was significantly related to low FIGO stage (pu200a=u200a0.001), less than 1/2 stromal invasion of the cervix (pu200a=u200a0.040), absent lymphatic invasion (pu200a=u200a0.026), and absent lymph node metastasis (pu200a=u200a0.003). In contrast, p53 expression was significantly related to advanced T stage (pu200a=u200a0.001), greater than 4u200acm for the greatest dimension of the tumour (pu200a=u200a0.002), more than 1/2 stromal invasion of the cervix (pu200a=u200a0.005), and poor survival (pu200a=u200a0.0218). Conclusions: TrkB and BDNF expression might play a significant role in the early events in tumorigenesis of cervical SCC. However, p53 is involved late in the process of tumour progression and therefore is predictive of a poor prognosis in SCC.

The effects of obesity and HER‐2 polymorphisms as risk factors for endometrial cancer in Korean women

Objectiveu2002 To evaluate the relationship between single nucleotide polymorphisms (SNPs) in the HER‐2 gene, body mass index (BMI) and the risk of endometrial cancer.

Lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system for endometrial cancer: a multi-center study.

BACKGROUNDnWe investigated whether pelvic or para-aortic lymphadenectomy increases the prognostic value of the revised 2009 FIGO staging system in patients with endometrial cancer (EC).nnnMETHODSnWe reviewed 786 patients with EC from six tertiary medical centers between July 1996 and June 2008. All patients were classified according to the 1988 FIGO staging system: IA (n = 234); IB (n = 270); IC (n = 109); IIA (n = 35); IIB (n = 29); IIIA (n = 37); IIIB (n = 3); IIIC (n = 69), and the revised 2009 FIGO staging system was also applied to divide them: IA (=542); IB (=125); II (n = 29); IIIA (n = 18); IIIB (n = 3); IIIC1 (n = 43); IIIC2 (n = 26). Prognostic values between the 1988 and the revised 2009 FIGO staging systems were compared by multivariate Coxs proportional hazard analysis.nnnRESULTSnThe 1988 FIGO stage IC, IIB, IIIA + IIIB and IIIC, and the revised 2009 FIGO stage IB, II, IIIA + IIIB and IIIC2 diseases were prognostic factors for poor PFS, whereas the 1988 FIGO stage IIB and IIIC, and the revised 2009 FIGO stage II, IIIA + IIIB and IIIC2 diseases were unfavorable prognostic factors for OS. Although these results were similar to those in 595 patients who underwent pelvic or para-aortic lymphadenectomy, the revised 2009 FIGO stage IIIC1 disease was an additional prognostic factor for poor PFS and OS (adjusted HRs, 4.19 and 11.25; 95% CIs, 1.39-12.60 and 2.23-36.74).nnnCONCLUSIONSnThe revised 2009 FIGO staging system had a higher prognostic value than the 1988 FIGO staging system, and pelvic or para-aortic lymphadenectomy increased the prognostic value of the revised 2009 FIGO staging system for EC.

Downregulation of GLTSCR2 expression is correlated with breast cancer progression.

Glioma tumor-suppressor candidate region gene2 (GLTSCR2) is a recently identified nucleolus-localized protein participating in the regulation of cell cycle progression and apoptosis. Down-regulation of GLTSCR2 in several types of cancers and increased transforming activity in GLTSCR2-downregulated cancer cells indicated its tumor suppressive potential. The aim of this study was to evaluate GLTSCR2 expression in breast cancer and to investigate the question of whether reduced expression of GLTSCR2 may have any pathological significance in breast cancer development or progression. In this study, we performed quantitative RT-PCR and immunohistochemistry to evaluate the expression of GLTSCR2 and relevance with clinicopathological factors in the invasive ductal carcinoma (IDC). GLTSCR2 expression was reduced in 48% of IDC (n=426) by a semi-quantitative scoring system using tissue microarray. GLTSCR2 mRNA was significantly reduced by 0.16 fold in 15 out of 17 (88%) cases of IDC. Reduction of GLTSCR2 was significantly correlated with increased histological grade (p<0.005), increased tumor size (p<0.001), axillary lymph node involvement (p<0.001) and decreased disease free survival (p<0.025). In addition, we show that upregulation of GLTSCR2 decreases the invasive potential of breast cancer cells. Taken together, our data suggest that GLTCR2 may play a role in the tumorigenesis, progression and biological behavior in breast cancer.

Tumoral FOXP3 has potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas

FOXP3 is a transcription factor and a well-known hallmark of immune suppressive T regulatory cells. Recent studies indicate that in tumor cells, FOXP3 plays an important role in tumor development in addition to its well-established Treg function in the immune system. We investigated tumoral FOXP3 expression in breast carcinoma, and the relationships between tumoral FOXP3 expression and p53, HER-2/ErbB2, Ki67, infiltrated Tregs, and other clinicopathological variables. Tissue samples from 272 cases of breast carcinoma were used. We assessed tumoral FOXP3, p53, HER-2/ErbB2, Ki67, and infiltrated Tregs using immunohistochemical staining. Positive expression of tumoral FOXP3 was observed in 38.6% (105/272) of breast carcinomas. Positive tumoral FOXP3 expression was significantly related with positive p53 and higher Ki67 expression. Higher histological grade was significantly correlated to increased tumoral FOXP3 expression. Tumoral FOXP3 expression was positively correlated with infiltrated FOXP3-expressing Tregs. From these data, we argue that tumoral FOXP3 has a potential oncogenic function in conjunction with the p53 tumor suppressor protein and infiltrated Tregs in human breast carcinomas.

Autophagy is related to the hedgehog signaling pathway in human gastric adenocarcinoma: prognostic significance of Beclin-1 and Gli2 expression in human gastric adenocarcinoma.

Beclin-1 induces autophagy, which is known to be involved in many physiopathological processes such as cell development, aging, stress response, immune response and cancer. Several studies showed that Beclin-1 expression is associated with several prognostic factors of gastric carcinomas. Recently, the connection between autophagy and the hedgehog (HH) signaling pathway has been studied. Here, we investigated the relationship between the autophagy and hedgehog (HH) signaling pathways in gastric adenocarcinoma. We evaluated Beclin-1 and Gli2 expression in 108 gastric adenocarcinoma tissues via immunohistochemical analysis, using a tissue microarray, in relation to survival and other prognostic factors. Our results show that increased Beclin-1 expression is correlated with favorable clinicopathological variables including histologic grade, tumor size, primary tumor (T) stage, lymph node metastasis, lymphatic invasion, neural invasion, and tumor recurrence. Furthermore, increased Gli-2 expression was correlated with several favorable clinicopathological variables including primary tumor (T) stage, lymphatic invasion, and tumor recurrence. Increased Beclin-1 expression was significantly correlated with increased Gli2. Univariate analyses for disease-free survival and overall survival revealed that the higher Beclin-1 and Gli2 expression group had a more favorable prognosis compared with the lower Beclin-1 and Gli2 expression group. Our results suggest that progressively increased Beclin-1 and Gli2 expression contributes to the inhibition of tumor growth and metastasis in gastric adenocarcinoma and Beclin-1 acts as a tumor suppressor by regulating the HH signaling pathway through Gli2 expression in gastric adenocarcinoma.