微生物促进膀胱尿路上皮细胞癌发生和发展分子机制的研究进展

膀胱尿路上皮细胞癌(urothelial carcinoma of bladder, UCB)是泌尿系统常见的恶性肿瘤,是膀胱癌(bladder cancer, BC)最常见的病理类型。UCB具有高发病率、高死亡率和易复发等特点,对人类健康构成巨大威胁。引发UCB的原因可能与吸烟和接触有毒化学物质有关,但是随着研究的不断深入,人们发现膀胱内存在独特的微生物群,它与UCB的发生和发展密切相关。本文着重综述微生物通过尿路感染(urinary tract infection, UTI)、影响上皮-间充质转化(epithelial-mesenchymal transition, EMT)以及上调细胞程序性死亡-配体1 (programmed cell death 1 ligand 1, PD-L1)的表达来参与UCB的发生和发展,同时也对健康人群与UCB患者微生物群特征以及UCB的预防和治疗等方面作了相应阐述。通过综述微生物与UCB之间的关系,为进一步明确微生物对UCB的促进作用以及研发治疗UCB的药物提供新思路。     

肿瘤转移抑制基因TIP30/CC3在膀胱尿路上皮癌中的作用

目的探讨膀胱尿路上皮癌中肿瘤转移抑制基因TIP30/CC3基因的表达及意义。方法收集武汉大学人民医院病理科2000-2006年有完整临床和病理资料的膀胱尿路上皮癌存档蜡块50例和5例癌旁组织,采用免疫组织化学S-P法检测50例膀胱尿路上皮癌和5例癌旁组织中TIP30/CC3基因的表达水平。并分析TIP30/CC3基因与膀胱尿路上皮癌临床和病理特征的关系。采用HPIAS-1000高清晰度彩色病理图文报告管理系统,对TIP30/CC3基因的表达进行定量分析,并用SPSS13.0软件对各组免疫组织化学反应阳性颗粒的平均光密度、阳性面积率做单因素方差分析和SNK(q)检验。结果 (1)TIP30/CC3基因在膀胱尿路上皮癌中呈低表达,癌旁组织中呈高表达。膀胱尿路上皮癌与癌旁组织相比,差异有显著性(P<0.05);(2)TIP30/CC3的表达与患者年龄、性别之间的差异均无显著性(P>0.05)。但与肿瘤浸润深度、分化程度和临床UICC分期之间的差异均有显著性(P<0.05)。结论抑癌基因TIP30/CC3基因在膀胱尿路上皮癌中的低表达可能促进了膀胱尿路上皮癌的发生和发展。     

DLL4和Notch4在膀胱尿路上皮癌中的表达及临床意义

目的探讨DLL4和Notch4在膀胱尿路上皮癌中的表达及其临床意义。方法收集福建医科大学附属第一医院2008-2010年有完整临床病理资料的膀胱尿路上皮癌存档蜡块85例和27例癌旁组织,采用组织芯片免疫组织化学法检测膀胱尿路上皮癌和癌旁组织DLL4和Notch4的表达水平。对DLL4和Notch4的表达进行半定量分析,并用SPSSl3．0软件对各组免疫组织化学反应阳性率采用x。检验或Fisher精确概率法分析。结果（1）DLL4和Notch4在膀胱尿路上皮癌中呈高表达,癌旁组织中呈低表达,差异有显著性（P〈O．05）。（2）Notch4和DLL4在膀胱尿路上皮癌中的表达与患者性别、年龄、临床分期、病理分级及初复发均无显著相关性（P〉0．05）。结论DLL4和Notch4在膀胱尿路上皮癌中的高表达与膀胱尿路上皮癌血管生成密切相关,阻断DLL4-Noteh4信号通路有望抑制膀胱尿路上皮癌的发生发展。     

Cancer metabolism,stemness and tumor recurrence

Here, we interrogated head and neck cancer (HNSCC) specimens (n = 12) to examine if different metabolic compartments (oxidative vs. glycolytic) co-exist in human tumors. A large panel of well-established biomarkers was employed to determine the metabolic state of proliferative cancer cells. Interestingly, cell proliferation in cancer cells, as marked by Ki-67 immunostaining, was strictly correlated with oxidative mitochondrial metabolism (OXPHOS) and the uptake of mitochondrial fuels, as detected via MCT1 expression (p < 0.001). More specifically, three metabolic tumor compartments were delineated: (1) proliferative and mitochondrial-rich cancer cells (Ki-67+/TOMM20+/COX+/MCT1+); (2) non-proliferative and mitochondrial-poor cancer cells (Ki-67−/TOMM20−/COX−/MCT1−); and (3) non-proliferative and mitochondrial-poor stromal cells (Ki-67−/TOMM20−/COX−/MCT1−). In addition, high oxidative stress (MCT4+) was very specific for cancer tissues. Thus, we next evaluated the prognostic value of MCT4 in a second independent patient cohort (n = 40). Most importantly, oxidative stress (MCT4+) in non-proliferating epithelial cancer cells predicted poor clinical outcome (tumor recurrence; p < 0.0001; log-rank test), and was functionally associated with FDG-PET avidity (p < 0.04). Similarly, oxidative stress (MCT4+) in tumor stromal cells was specifically associated with higher tumor stage (p < 0.03), and was a highly specific marker for cancer-associated fibroblasts (p < 0.001). We propose that oxidative stress is a key hallmark of tumor tissues that drives high-energy metabolism in adjacent proliferating mitochondrial-rich cancer cells, via the paracrine transfer of mitochondrial fuels (such as L-lactate and ketone bodies). New antioxidants and MCT4 inhibitors should be developed to metabolically target “three-compartment tumor metabolism” in head and neck cancers. It is remarkable that two “non-proliferating” populations of cells (Ki-67−/MCT4+) within the tumor can actually determine clinical outcome, likely by providing high-energy mitochondrial “fuels” for proliferative cancer cells to burn. Finally, we also show that in normal mucosal tissue, the basal epithelial “stem cell” layer is hyper-proliferative (Ki-67+), mitochondrial-rich (TOMM20+/COX+) and is metabolically programmed to use mitochondrial fuels (MCT1+), such as ketone bodies and L-lactate. Thus, oxidative mitochondrial metabolism (OXPHOS) is a common feature of both (1) normal stem cells and (2) proliferating cancer cells. As such, we should consider metabolically treating cancer patients with mitochondrial inhibitors (such as Metformin), and/or with a combination of MCT1 and MCT4 inhibitors, to target “metabolic symbiosis.”     

Correlations between glycolysis with clinical traits and immune function in bladder urothelial carcinoma

Background: Glycolysis was a representative hallmark in the tumor microenvironment (TME), and we aimed to explore the correlations between glycolysis with immune activity and clinical traits in bladder urothelial carcinoma (BLCA).Methods: Our study obtained glycolysis scores for each BLCA samples from TCGA by a single-sample gene set enrichment analysis (ssGSEA) algorithm, based on a glycolytic gene set. The relationship between glycolysis with prognosis, clinical characteristics, and immune function were investigated subsequently.Results: We found that enhanced glycolysis was associated with poor prognosis and metastasis in BLCA. Moreover, glycolysis had a close correlation with immune function, and enhanced glycolysis increased immune activities. In other words, glycolysis had a positive correlation with immune activities. Immune checkpoints such as IDO1, CD274, were up-regulated in high-glycolysis group as well.Conclusion: We speculated that in BLCA, elevated glycolysis enhanced immune function, which caused tumor cells to overexpress immune checkpoints to evade immune surveillance. Inhibition of glycolysis might be a promising assistant for immunotherapy in bladder cancer.     

Metabolic reprogramming and epigenetic modifications on the path to cancer

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.Supplementary InformationThe online version contains supplementary material available at (10.1007/s13238-021-00846-7) contains supplementary material, which is available to authorized users.     

Identification of five long noncoding RNAs signature and risk score for prognosis of bladder urothelial carcinoma

Nowadays, an increasing number of studies illustrated that bladder urothelial cancer (BLCA) may act as the most common subtype of urological malignancies with a high rate of recurrence and metastasis. In this study, we attempted to establish a prognostic model and identify the possible pathway crosstalk. Long noncoding RNAs (lncRNAs) and mRNA expression and corresponding clinical information of patients with BLCA were downloaded from The Cancer Genome Atlas (TCGA). The differentially expressed genes analysis, univariate Cox analysis, the least absolute shrinkage, and selection operator Cox (LASSO Cox) regression model were then applied to identify five crucial lncRNAs (AC092725.1, AC104071.1, AL023584.1, AL132642.1, and AL137804.1). The multivariate cox analysis was utilized to calculate the regression coefficients (β_i). The risk-score model was subsequently constructed as follows: (0.13541AC092725.1) + (0.20968AC104071.1) + (0.1525AL023584.1) − (0.14768AL132642.1) + (0.14387AL137804.1). Nomogram and assessment of overall survival (OS) prediction were verificated by the receiver operating characteristic curve in the testing group. As to 3-, 5-year OS prediction, the area under curve (AUC) for the nomogram of training data set was 0.83 and 0.86. Besides, the AUC (0.883 and 0.879) presented excellent predictive power in the testing group. In addition, the calibration plots validated the predictive performance of the nomogram. Weighted correlation network analysis (WGCNA) coupled with functional enrichment analysis contributed to explore the potential pathways, including PI3K-Akt, HIF-1, and Jak-STAT signaling pathways. Construction of the risk-score model and data analysis were both derived from multiple packages on the basis of the R platform chiefly.     

Over-expression of fibroblast activation protein alpha increases tumor growth in xenografts of ovarian cancer cells

Fibroblast activation protein alpha （FAPα） is a 95-kDa serine protease of post-prolyl peptidase family on cell surface. FAPoL is widely expressed in tumor microenviron- ment. The wide spread association of FAPα expression with cancer suggests that it has important functions in the disease. However, the nature of FAPα＇s roles in cancer cell activity is not well-determined. It has been showed that FAPα silencing in SKOV3 cells induces ovarian tumors but significantly reduces tumor growth in a xenograft mouse model. To further determine the role of FAPoL in epithelial ovarian cancer cells, SKOV3-FAPα and HO8910-FAPα cell lines, which over-expressed FAPα stably, were con- structed and then their biological behaviors were investi- gated. It was found that FAPoL promoted ovarian cancer cell proliferation, drug resistance, invasiveness, and migra- tion in vitro. Immunochemistry assay showed that FAPα significantly facilitated tumor growth in xenograft tumor tissues. These results suggested that FAPα might directly promote tumor growth and invasiveness in ovarian cancer cells.     

Cytokine gene polymorphisms are associated with risk of urinary bladder cancer and recurrence after BCG immunotherapy

The association of interleukin-1β (IL-1B) -511C?>?T and IL-1 receptor antagonist (IL-1RN) VNTR, transforming growth factor-β (TGF-B1) +28C?>?T and interferon-γ (IFN-G)?+?874T>A polymorphisms with bladder cancer (CaB) susceptibility and risk of recurrence in Bacillus Calmette–Guérin (BCG)-treated patients was analyzed in 287 controls and 213 CaB patients (73 BCG treated). Increased risk was observed with the IL-1RN*2 allele (odds ratio (OR) 5.01) and the IFN-G +874 A allele (OR 1.78). TGF-B TT and IFN-G +874 A carriers were associated with reduced (hazard ratio (HR) 0.37) and enhanced (HR 2.24) risk of recurrence after BCG immunotherapy, respectively. The study suggests that cytokine gene variants may modulate CaB susceptibility and risk of recurrence after BCG immunotherapy.     

Prostasin may contribute to chemoresistance,repress cancer cells in ovarian cancer,and is involved in the signaling pathways of CASP/PAK2-p34/actin

Ovarian cancer is the deadliest of gynecologic cancers, largely due to the development of drug resistance in chemotherapy. Prostasin may have an essential role in the oncogenesis. In this study, we show that prostasin is decreased in an ovarian cancer drug-resistant cell line and in ovarian cancer patients with high levels of excision repair cross-complementing 1, a marker for chemoresistance. Our cell cultural model investigation demonstrates prostasin has important roles in the development of drug resistance and cancer cell survival. Forced overexpression of prostasin in ovarian cancer cells greatly induces cell death (resulting in 99% cell death in a drug-resistant cell line and 100% cell death in other tested cell lines). In addition, the surviving cells grow at a much lower rate compared with non-overexpressed cells. In vivo studies indicate that forced overexpression of prostasin in drug-resistant cells greatly inhibits the growth of tumors and may partially reverse drug resistance. Our investigation of the molecular mechanisms suggests that prostasin may repress cancer cells and/or contribute to chemoresistance by modulating the CASP/P21-activated protein kinase (PAK2)-p34 pathway, and thereafter PAK2-p34/JNK/c-jun and PAK2-p34/mlck/actin signaling pathways. Thus, we introduce prostain as a potential target for treating/repressing some ovarian tumors and have begun to identify their relevant molecular targets in specific signaling pathways.