The Clinical Relevance of the Expression of SGLT2 in Lung Adenocarcinoma.

PURPOSE: We aimed to elucidate the functions and clinical relevance of sodium-glucose cotransporter 2 (SGLT2) in resected lung adenocarcinoma. METHODS: The protein expression of SGLT2 in tumor samples from 199 patients with lung adenocarcinoma was analyzed by immunohistochemistry, and the protein expression, clinical variables, and survival outcomes were compared. RESULTS: The median SGLT2 expression was significantly higher in advanced-stage and more aggressive adenocarcinomas. Age ≥70 (p < 0.01), BI ≥600 (p < 0.01), PRDX4 <25 (p < 0.01), and SGLT2 ≥12% (p = 0.03) were significant factors for RFS in multivariate analysis. Significant differences were observed in the RFS rates of the groups divided using the cutoff value of SGLT2 ≥12% (5-year RFS: 72.6% vs. 90%) (p < 0.01). CONCLUSION: The expression of SGLT2 was more frequently detected in advanced-stage and more aggressive adenocarcinomas with aggressive biological behavior than in their counterparts. The survival analysis revealed that the strong expression of SGLT2 was associated with poorer RFS. The SGLT2 expression predicts postoperative recurrence in lung adenocarcinoma patients.

PCBP1 acts as a regulator of CCL2 expression in macrophages to induce recruitment of monocyte-derived macrophages into the inflamed colon.

Intestinal macrophages with functional plasticity play essential roles in gut immune responses by increasing chemokines and cytokines, thereby contributing to the pathogenesis of inflammatory bowel disease (IBD). Poly(rC)-binding protein 1 (PCBP1), which is widely expressed in immune cells, binds to nucleic acids in mRNA processing, stabilization, translation and transcription. However, little is known about the influence of PCBP1 on macrophages and its specific mechanism in inflamed intestines. In this study, conditional depletion of Pcbp1 in macrophages protected mice from progression of dextran sulfate sodium induced colitis and resulted in significant alleviation of colitis. Pcbp1 deficiency markedly decreased C-C motif chemokine ligand 2 (CCL2) production by colonic CX3C motif chemokine receptor 1+ (CX3CR1+) macrophages and reduced accumulation of pro-inflammatory macrophages and production of pro-inflammatory cytokines, such as IL-6 and TNF-α, in the inflamed colon. RNA-immunoprecipitation analysis indicated that PCBP1 might interact with Ccl2 mRNA and regulate its expression in macrophages. PCBP1 expression in inflamed intestines also correlated significantly with IBD severity in patients, suggesting a critical involvement of PCBP1 in intestinal inflammation. We anticipate that our findings will facilitate the development of novel therapeutic approaches for IBD by targeting the specific function of immune cells in the local microenvironment, thereby helping to reduce adverse effects.

Epstein-Barr Virus-Positive Cutaneous and Systemic Plasmacytosis with TAFRO Syndrome-like Symptoms Successfully Treated with Rituximab.

Histopathologic findings in the lymph nodes of patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome are similar to those of idiopathic multicentric Castleman's disease (iMCD), but TAFRO syndrome is different from iMCD in how it can progress rapidly and be fatal. These patients present scarce lymphadenopathy and low immunoglobulin levels. We present a case of cutaneous and systemic plasmacytosis (C/SP) that caused TAFRO syndrome-like symptoms which were successfully treated with rituximab. A 67-year-old woman presented with fever and a pruritic skin rash. Numerous plasma cells were observed in the peripheral blood and imaging revealed organomegaly, anasarca, and generalized lymphadenopathy. Subsequently, she rapidly developed thrombocytopenia as well as renal and heart failure. She tested positive for the Epstein-Barr virus (EBV), elevated immunoglobulins, and C/SP, which are also atypical for TAFRO syndrome, thereby complicating the diagnosis. However, after using the Japanese TAFRO Syndrome Research Group diagnostic criteria, we promptly administered rituximab to treat the C/SP with TAFRO-like symptoms and saved her life. Finally, histopathological observations of the lymph node biopsy helped confirm EBV-positive hypervascular-type iMCD. Therefore, diagnosing TAFRO-like syndromes based on the Japanese diagnostic criteria and following the associated treatment even without a confirmed diagnosis is crucial to improving the patient outcomes.

The Detection of Immunity against WT1 and SMAD4P130L of EpCAM+ Cancer Cells in Malignant Pleural Effusion.

Malignant pleural effusion (MPE) provides a liquid tumor microenvironment model that includes cancer cells and immune cells. However, the characteristics of tumor antigen-specific CD8+ T cells have not been investigated in detail. Here, we analyzed MPE samples taken from a patient with pancreatic cancer who received a dendritic cell vaccine targeting Wilms' Tumor 1 (WT1) antigen over the disease course (two points at MPE1st and 2nd, two months after MPE1st). Epithelial cell adhesion molecule (EpCAM)+ cancer cells (PD-L1- or T cell immunoglobulin mucin-3, TIM-3-), both PD-1 or TIM-3 positive CD8+ T cells, and CD14+CD68+CD163+TIM-3+ macrophages increased from the MPE1st to MPE2nd. The ratio of WT1-specific cytotoxic lymphocytes (WT1-CTLs) to MPE CD8+ T cells and IFN-γ secretion of WT1-CTLs were reduced with disease progression. Coincidentally, the fraction of central memory T (TCM) of WT1-CTLs was decreased. On the other hand, CD8+ T cells in response to SMAD4P130L, which is homogeneously expressed in EpCAM+ cancer cells, were detected using in vitro expansion with the HLA-A*11:01 restrictive SVCVNLYH neoantigen. Furthermore, the CD8+ T cell response to SMAD4P130L was diminished following remarkably decreased numbers of CD8+ TCM in MPE samples. In conclusion, CD8+ T cells responding to WT1 or SMAD4P130L neoantigen expressed in EpCAM+ pancreatic cancer cells were detected in MPE. A tumor antigen-specific immune response would provide novel insight into the MPE microenvironment.

[Endocardial Blood Cyst in the Right Atrium:Report of a Case].

A 74-years-old man visited our hospital complaining chest discomfort, and he was diagnosed with variant angina. However, during close examination, a tumor with some small calcified nodules was accidentally pointed out in the right atrium. We carried out surgical removal to prevent embolism. A cystic tumor attached to the atrial septum was resected together with the atrial septum, and the defect was closed with a Dacron patch. The tumor size was 18×25×3 mm. Histologically, its wall was consisted of connective tissue, which was positive for CD34, negative for calretinin, and was diagnosed as an endocardial blood cyst. A core of the nodules in the cyst were calcified and they were phleboliths. Postoperative echocardiography detected no residual mass or atrial septal defect, and he was discharged uneventfully.

Overexpression of Teashirt Homolog 2 suppresses cell proliferation and predicts the favorable survival of Lung Adenocarcinoma.

Background: Teashirt homolog 2 (TSHZ2) is essential for maintaining cellular homeostasis and regulating transcription on neoplasia development. However, the regulation of TSHZ2 in lung tumorigenesis and the underlying mechanisms remain unclear. Objective: To evaluate the relationship between TSHZ2 expression in patients' tumor tissue and prognosis in lung adenocarcinoma. Methods: TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue were detected by Western blotting. The effect of TSHZ2 on cell proliferation, apoptosis and migration in lung adenocarcinoma cells was measured by CCK8, colony formation, flowcytometric analyses and wound-healing, respectively. TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue from patients was detected using Western blotting and immunohistochemical staining. We also retrospectively analyzed 226 lung adenocarcinoma patients after surgical resection using immunohistochemical staining, and the association of TSHZ2 expression with the patient survival was evaluated. Results: TSHZ2 was lowly expressed in certain lung adenocarcinoma cell lines (PC9 and B203L), but other cells showed a high expression. Low expression of TSHZ2 was also observed in most lung adenocarcinoma tissues compared with adjacent tissues. Furthermore, we found that the overexpression of TSHZ2 plasmids led to the dramatic inhibition of cell proliferation, colony formation ability, migration and apoptosis induction in PC9 lung adenocarcinoma cells. In contrast, no obvious effect was found when the TSHZ2 expression was down-regulated by si-TSHZ2. An elevated TSHZ2 expression was observed in 155(68.6%) tumor tissues samples of lung adenocarcinoma patients. Notably, the lung adenocarcinoma patients with a high TSHZ2 expression tended to have EGFR mutations less frequently and a preferable prognosis to those with a lower expression. Conclusion: A high TSHZ2 expression inhabited cell proliferation and predicted a better prognosis of lung adenocarcinoma, possibly representing a useful therapeutic target for lung adenocarcinoma.

New additional scoring formula on the Pathological Features in Stage I Lung Adenocarcinoma Patients: Impact on Survival.

Background: Histological heterogeneity of lung adenocarcinoma may result in different prognosis among patients with the same TNM pathological stage. However, no objective evaluation system of lung adenocarcinoma based on pathological features has been widely accepted for assessing the prognosis. Methods: We retrospectively analyzed 179 patients with stage I lung adenocarcinoma after complete surgical resection. The pathological classification was according to the IASLC/ATS/ERS adenocarcinoma classifications, and the detailed abundance ratio using HE staining of primary tumor specimens was recorded. A new additional scoring formula on the pathological features (ASP) was established. The association of the ASP score with the patients' survival was examined. Results: The ASP scoring was significantly associated with smoking history (p=0.004), lymphatic vessel invasion (p<0.001), vascular invasion, differentiation (p<0.001) and Ki67 (p<0.001). The patients in the high-ASP-score group tended to have vascular invasion (odds ratio [OR]: 1.637, 95% confidence interval [CI]: 1.923-13.745, p=0.001) and high Ki67 expression (OR: 2.625, 95%CI: 1.328-5.190, p=0.006) by logistic regression analyses. The prognosis differed significantly in the Kaplan-Meier survival curves, and the 5-year survival rates in the low and high ASP score groups were 97.8% and 89.6%, respectively (p=0.018). Based on the univariate analysis, female (OR: 0.111, 95%CI: 0.014-0.906, p=0.040), long smoking history (OR: 7.250, 95%CI: 1.452-36.195, p=0.016), poor differentiation characteristics correlation (OR: 12.691, 95%CI: 1.557-103.453, p=0.018), and high ASP score (OR: 5.788, 95%CI: 1.138-29.423, p=0.034) were shown to be independently associated with an unfavorable prognosis. Conclusion: The ASP score can effectively screen high-risk patients for complete surgical resection of stage I lung adenocarcinoma.

Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease?

Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8-associated, POEMS syndrome-associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO-iMCD), whereas iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO-w/op-iMCD). To clarify the clinical features of iMCD-NOS, TAFRO-iMCD, and TAFRO-w/op-iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD-NOS, 63 with TAFRO-iMCD, and 19 with TAFRO-w/op-iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C-reactive protein and interleukin-6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO-iMCD, and TAFRO-w/op-iMCD groups. However, the iMCD-NOS group exhibited polyclonal hyper-γ-globulinemia. The five-year survival rates of patients in the iMCD-NOS and TAFRO-involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD-NOS and the TAFRO-iMCD samples typically showed plasma cell and mixed-type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD-NOS and TAFRO-iMCD. As such, TAFRO-iMCD and TAFRO-w/op-iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.

Rhabdomyosarcoma arising from retroperitoneal teratoma in an infantile neurofibromatosis type 1 patient.

We herein report the case of a 2-year-old girl with neurofibromatosis type 1 (NF1), who presented with a 12-cm mass in the right retroperitoneum and underwent tumor resection. Histologically, the tumor was composed of two distinct components: one was teratoma, showing mature morphology; and the other was embryonal rhabdomyosarcoma. An interphase fluorescence in situ hybridization (FISH) analysis of the rhabdomyosarcoma component revealed the absence of isochromosome 12p. Although it is well known that rhabdomyosarcoma occurs in infantile NF1, and that rhabdomyosarcoma can arise from teratoma as a somatic-type malignancy, to the best of our knowledge, this is the first case of an infantile NF1 patient, who developed rhabdomyosarcoma within a retroperitoneal teratoma. The absence of chromosome 12p alteration suggests a possibility that the rhabdomyosarcoma occurred due to the NF1 background, not as a somatic-type malignancy of germ cell tumor.

The impact of PRDX4 and the EGFR mutation status on cellular proliferation in lung adenocarcinoma.

Background: Oxidative stress plays key roles in the progression of lung adenocarcinoma. Recently, we reported that peroxiredoxin 4 (PRDX4), an antioxidant enzyme, can be a prognostic marker of lung adenocarcinoma (LUAD). In the present study, we aimed to further investigate the relationship among the PRDX4 expression, epidermal growth factor receptor (EGFR) mutations and cell proliferation in LUAD. Methods: The expression of PRDX4 was immunohistochemically analyzed and the EGFR mutation status was examined in 127 paraffin-embedded human surgical specimens from patients with stage I LUAD. The PRDX4 expression was considered to be high when >40% of the adenocarcinoma cells were positively stained. In vitro, using plasmid transfection methods, PRDX4 plasmid DNAs were transfected into human lung adenocarcinoma cell lines, A549 (EGFR-wild) or PC-9 (EGFR mutant). The viability of these cells was analyzed using a Cell Counting Kit-8 kit. Results: The number of cases with high PRDX4 expression levels among patients with LUAD with EGFR mutations was significantly larger than that in patients with EGFR wild-type. The combination of the PRDX4 expression level with the EGFR mutation status was closely associated with the prognosis of patients with stage I LUAD. Viability assays showed that the proliferation of A549 cells was significantly suppressed after PRDX4 plasmid transfection, while the overexpression of PRDX4 had no effect on the proliferation of EGFR-mutant PC-9 cells. Conclusions: The PRDX4 expression and EGFR mutation status were significantly associated with the prognosis of patients with stage I LUAD, and EGFR mutations affected the role of PRDX4 in the proliferation of LUAD cells.

Depletion of WNT10A Prevents Tumor Growth by Suppressing Microvessels and Collagen Expression.

Background: We recently reported that WNT10A plays a pivotal role in wound healing by regulating collagen expression/synthesis, as the depletion of WNT10A dramatically delays skin ulcer formation. WNT signaling also has a close correlation with the cancer microenvironment and proliferation, since tumors are actually considered to be 'unhealing' or 'overhealing' wounds. To ascertain the in vivo regulatory functions of WNT10A in tumor growth, we examined the net effects of WNT10A depletion using Wnt10a-deficient mice (Wnt10a -/-). Methods and Results: We subjected C57BL/6J wild-type (WT) or Wnt10a -/- mice to murine melanoma B16-F10 cell transplantation. Wnt10a -/- mice showed a significantly smaller volume of transplanted melanoma as well as fewer microvessels and less collagen expression and more necrosis than WT mice. Conclusions: Taken together, our observations suggest that critical in vivo roles of Wnt10a-depleted anti-stromagenesis prevent tumor growth, in contrast with true wound healing/scarring.

Protective Role of Myelocytic Nitric Oxide Synthases against Hypoxic Pulmonary Hypertension in Mice.

RATIONALE: Nitric oxide (NO), synthesized by NOSs (NO synthases), plays a role in the development of pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains elusive. OBJECTIVES: To determine the role of NOSs in BM cells in PH. METHODS: Experiments were performed on 36 patients with idiopathic pulmonary fibrosis and on wild-type (WT), nNOS (neuronal NOS)-/-, iNOS (inducible NOS)-/-, eNOS (endothelial NOS)-/-, and n/i/eNOSs-/- mice. MEASUREMENTS AND MAIN RESULTS: In the patients, there was a significant correlation between higher pulmonary artery systolic pressure and lower nitrite plus nitrate levels in the BAL fluid. In the mice, hypoxia-induced PH deteriorated significantly in the n/i/eNOSs-/- genotype and, to a lesser extent, in the eNOS-/- genotype as compared with the WT genotype. In the n/i/eNOSs-/- genotype exposed to hypoxia, the number of circulating BM-derived vascular smooth muscle progenitor cells was significantly larger, and transplantation of green fluorescent protein-transgenic BM cells revealed the contribution of BM cells to pulmonary vascular remodeling. Importantly, n/i/eNOSs-/--BM transplantation significantly aggravated hypoxia-induced PH in the WT genotype, and WT-BM transplantation significantly ameliorated hypoxia-induced PH in the n/i/eNOSs-/- genotype. A total of 69 and 49 mRNAs related to immunity and inflammation, respectively, were significantly upregulated in the lungs of WT genotype mice transplanted with n/i/eNOSs-/--BM compared with those with WT-BM, suggesting the involvement of immune and inflammatory mechanisms in the exacerbation of hypoxia-induced PH caused by n/i/eNOSs-/--BM transplantation. CONCLUSIONS: These results demonstrate that myelocytic n/i/eNOSs play an important protective role in the pathogenesis of PH.

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear. METHODS: Serum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration. RESULTS: Serum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice. CONCLUSIONS: PRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

Peroxiredoxin 4 (PRDX4): Its critical in vivo roles in animal models of metabolic syndrome ranging from atherosclerosis to nonalcoholic fatty liver disease.

The peroxiredoxin (PRDX) family, a new family of proteins with a pivotal antioxidative function, is ubiquitously synthesized and abundantly identified in various organisms. In contrast to the intracellular localization of other family members (PRDX1/2/3/5/6), PRDX4 is the only known secretory form and protects against oxidative damage by scavenging reactive oxygen species in both the intracellular (especially the endoplasmic reticulum) compartments and the extracellular space. We generated unique human PRDX4 (hPRDX4) transgenic (Tg) mice on a C57BL/6J background and investigated the critical and diverse protective roles of PRDX4 against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease (NAFLD) as well as evaluated its role in the intestinal function in various animal models. Our published data have shown that PRDX4 helps prevent the progression of metabolic syndrome by reducing local and systemic oxidative stress and synergistically suppressing steatosis, inflammatory reactions, and/or apoptotic activity. These observations suggest that Tg mice may be a useful animal model for studying the relevance of oxidative stress on inflammation and the dysregulation of lipid/bile acid/glucose metabolism upon the progression of human metabolic syndrome, and that specific accelerators of PRDX4 may be useful as therapeutic agents for ameliorating various chronic inflammatory diseases.

The Combination Of Weak Expression Of PRDX4 And Very High MIB-1 Labelling Index Independently Predicts Shorter Disease-free Survival In Stage I Lung Adenocarcinoma.

Background: Oxidative stress plays pivotal roles in the progression of lung adenocarcinoma (LUAD) through cell signaling related closely to cancer growth. We previously reported that peroxiredoxin 4 (PRDX4), a secretory-type antioxidant enzyme, can protect against the development of various diseases, including potential malignancies. Since many patients with early-stage LUAD develop recurrence, even after curative complete resection, we investigated the association of the PRDX4 expression with the clinicopathological features and recurrence/prognosis using post-surgical samples of stage I-LUAD. Methods: The expression of PRDX4 and MIB-1, a widely accepted Ki67 protein, was immunohistochemically analysed in 206 paraffin-embedded tumour specimens of patients with stage I-LUAD. The PRDX4 expression was considered to be weak when less than 25% of the adenocarcinoma cells showed positive staining. Results: A weak PRDX4+ expression demonstrated a significantly close relationship with pathologically poor differentiation, highly invasive characteristics and recurrence. The decrease in PRDX4-positivity potentially induced cell growth in LUAD, which was correlated significantly with a very high MIB-1 labelling index (≥17.3%). Univariate/multivariate analyses revealed that the subjects with both weak PRDX4+ expression and a very high MIB-1 index had significantly worse disease-free survival rates than other subjects. Conclusions: The combination of weak PRDX4 expression and a very high MIB-1 index can predict high proliferating activity and recurrence with a potential poor prognosis, especially in post-operative stage I-LUAD patients.

Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury.

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

CD163-positive cancer cells are potentially associated with high malignant potential in clear cell renal cell carcinoma.

CD163 is preferentially expressed by monocyte/macrophages; however, recent studies using immunohistochemistry (IHC) have reported that some cancer cells also express CD163. In the present IHC study, we investigated CD163 staining of cancer cells and macrophages in clear cell renal cell carcinoma (ccRCC) tissues and determined the relationship between cancer cell CD163 expression and clinical prognosis in patients with ccRCC. IHC for CD163 was performed in ccRCC tissues from 103 patients. CD163-positive cancer cells were detected in 35% of the patients (36/103); however, the positive signals on cancer cells were significantly lower than those on macrophages. CD163-positive cancer cells were preferentially detected in patients with high T classification, and females, and were significantly associated with shortened progression-free survival and a lower overall survival ratio. Notably, a high intensity of CD163-positive macrophage infiltration was detected in the CD163-positive cancer cell-high tumor areas. Although CD163 mRNA was detected in cultured macrophages, no CD163 mRNA was detected in two cultured RCC cell lines. The detailed mechanism by which a positive signal is detected on cancer cells has not been clarified. Detection of the CD163 antigen on cancer cells might be a useful marker for evaluating the clinical course of patients with ccRCC.

Association of Casp3 microRNA Target Site (1049216) SNP With the Risk and Progress of Cervical Squamous Cell Carcinoma.

OBJECTIVE: In the present study, we investigated the relationship between the single-nucleotide polymorphism (SNP) of caspase-3 rs1049216 (C > T), a miRNA target site, and the risk and progression of cervical cancer. MATERIALS AND METHODS: Using polymerase chain reaction-restriction fragment length polymorphism, we evaluated the genotype and distribution of caspase-3 rs1049216 in 515 patients with cervical squamous cell cancer and 415 controls. In additional experiments, we transfected luciferase reporter plasmids carrying T or C allele and/or miRNA mimics into the human cervical cell lines (HeLa and C-33A) to analyze its roles in the regulation of caspase-3 expression. By immunohistochemistry, the protein level of caspase-3 expression was examined in tumor tissues from 515 patients with cervical squamous cell cancer. RESULTS: We found that the TT genotype of caspase-3 rs1049216 conferred a significantly decreased risk of cervical cancer (adjusted odds ratio, 0.35; 95% confidence interval, 0.154-0.581) and may be associated with the progression of this cancer. Although the expression of caspase-3 in the TT genotype was higher than that in CC/CT genotype in peripheral blood mononuclear cells and tumor tissues. Additional luciferase analysis showed that the rs1049216 variant T allele was associated with significantly higher luciferase activity, compared with the C allele in the transfected cells, and when cotransfected with miRNAs, miRNA-181a could downregulate the luciferase activity in the cells that transfected the construct containing C allele, compared with T allele, which had not happened in the presence of other miRNAs selected. CONCLUSIONS: These data indicate that through upregulating the expression of caspase-3, the TT genotype of caspase-3 rs1049216 can be associated with not only the risk of cervical cancer but also the progression of this cancer.