Long-term survival in uterine clear cell carcinoma and uterine papillary serous carcinoma

Uterine clear cell carcinoma (UCC) and uterine papillary serous carcinoma (UPSC) are rare entities that differ in clinical behavior from endometrial adenocarcinoma. Compared with endometrioid adenocarcinoma, they more often metastasize early and more commonly in the upper abdomen including the omentum. Treatment programs of UCC and UPSC at different stages vary and range from no adjuvant therapy in stage Ia to a wide variety of chemotherapies and radiotherapies in more advanced stages. This study presents the outcome of 109 patients with UCC or UPSC treated according to essentially the same treatment program from May 1993 to December 2004. Most patients were treated with a simple hysterectomy with no further adjuvant treatment. In stage Ia, 2/46 patients died of their disease and amongst all the stages, 30/109 patients died of their disease. These survival outcomes are comparable to or better than those presented previously.     

RBM4 inhibits the growth of clear cell renal cell carcinoma by enhancing the stability of p53 mRNA

RBM4 has been reported as a tumor suppressor gene in cancers, including lung cancer, colon cancer and gastric cancer. However, the role of RBM4 in clear cell renal cell carcinoma (ccRCC) remains unclear. Therefore, the present study investigated the expression and biological function of RBM4 in ccRCC. Analysis of the differential expression of RBM4 and its relationship with clinicopathological features using ccRCC samples data from TCGA database deminstrated that RBM4 expression in tumor samples of ccRCC was lower than that in normal samples, and RBM4 expression was closely related to the survival time of patients. RBM4 overexpression (RBM4-oe) cell lines were constructed to investigate the effect of RBM4 on biological function using CCK-8, EdU, flow cytometry and wound-healing assays. In addition, the regulatory effect of RBM4 on signaling pathways was investigated by GSEA and WB assays. RBM4-oe significantly reduced the proliferation of ccRCC cells by controlling the p53 signaling pathway, inhibited cell cycle progression and promoted apoptosis. In addition, RBM4-oe suppressed the migration and invasion of cells by EMT. Mechanistically, RBM4-oe facilitated the activity of the p53 signaling pathway by enhancing the stability of p53 mRNA. Finally, RBM4-oe markedly inhibited the growth of tumors formed with 786-O cells in vivo. In summary, there findings suggeated that RBM4 inhibits the progression of ccRCC by promoting p53 signaling pathway activity by enhancing the stability of p53 mRNA, suggesting that RBM4 may be a potential target for the treatment of patients.     

Impact of iASPP on chemoresistance through PLK1 and autophagy in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo‐like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival. The growth of OCCC cell lines, OVTOKO and KK, were inhibited after iASPP silencing. Such effect was related to senescence triggering as evidenced by increased SA‐β‐Gal staining and p21^WAF1/Cip1 expression. Moreover, knockdown of iASPP induced PLK1 downregulation, whereas either genes’ silencing sensitized the cells in response to cisplatin treatment. More prominent apoptosis was induced by cisplatin in OCCC cells after the knockdown of either iASPP or PLK1 as evidenced by the formation of more cleaved caspase 3. Heightened chemosensitivity to cisplatin after iASPP knockdown was further demonstrated in in vivo xenograft model. Additionally, both iASPP and PLK1 were shown to regulate autophagic flux as the induction of LC3B‐II and LC3 puncta were much less in OCCC cells with either knockdown. Importantly, inhibition of autophagy also enhanced chemosensitivity to cisplatin in OCCC cells. These findings strongly imply that iASPP and PLK1 affect the chemoresistance of OCCC via the regulation of autophagy and apoptosis. Both iASPP and PLK1 can be potential therapeutic targets for treating OCCC in combination with conventional chemotherapy.     

Epigenetic silencing of ASPP1 confers 5‐FU resistance in clear cell renal cell carcinoma by preventing p53 activation

Inactivation of p53 has been shown to correlate with drug resistance in tumors. However, in clear cell renal cell carcinoma (ccRCC), p53 is rarely mutated, yet the tumors remain highly insensitive to the conventional chemotherapeutic drugs. The underlying mechanisms responsible for the non‐genetic p53 inactivation remain obscure. Here, we report, for the first time, that Apoptosis Stimulating of P53 Protein 1 (ASPP1) was remarkably downregulated at both mRNA (about 3.9‐fold) and protein (about 4.9‐fold) levels in ccRCC human specimens in comparison with the paired normal controls. In addition, lower ASPP1 was closely related to the higher grade of tumors and shorter life expectancy of ccRCC patients, both with p < 0.001. We also find that CpG island hypermethylation at promoter region contributed to the suppression of ASPP1 expression in ccRCC that contained relatively low levels of ASPP1. Further functional studies demonstrated that forced expression ASPP1 not only significantly inhibited the growth rate of ccRCC, but also promoted sensitivity of ccRCC to the conventional chemotherapeutic drug 5‐fluorouracil (5‐FU)‐induced apoptosis. Moreover, ASPP1 expression was accompanied with the apoptosis‐prone alterations of p53 targets expression and p53 target PIG3 luciferase reporter activation. In contrast, ASPP1 knockdown promoted cell growth and prevent 5‐FU‐induced p53 activation and apoptosis. In conclusion, our results suggest that ASPP1 silencing is one of dominate mechanisms in inhibiting wild type p53 in ccRCC. ASPP1, therefore, may be potentially used as a promising biomarker for prognosis and therapeutic intervention in ccRCC.     

p53 polymorphic variants at codon 72 exert different effects on cell cycle progression

Two common polymorphic forms of the p53 tumor suppressor protein are widely distributed throughout the human population. These encode either proline or arginine at position 72, and this difference results in a marked alteration in the primary structure of the protein. A number of previous studies have shown significant differences in the biochemical properties of the p53 protein, depending on the particular polymorphic form. There is little information, however, on their respective biologic activities. In this study, we have used an inducible switch system for expressing both polymorphic forms of p53 within Saos-2 cells. Cell cycle analysis postinduction of p53 function reveals striking differences in how the 2 forms of p53 bring about a cessation of cell growth. Thus, the Arg72 form of p53 is significantly more efficient than the Pro72 form at inducing apoptosis. In contrast, the Pro72 form appears to induce a higher level of G1 arrest than the Arg72 form. These results demonstrate significant differences in how the codon 72 polymorphism affects the biological activity of p53.     

New perspectives on molecular targeted therapy in ovarian clear cell carcinoma

Ovarian clear cell carcinomas (OCCCs) account for about 5–13% of all epithelial ovarian carcinomas in Western populations. It is characterised by resistance to conventional platinum-based chemotherapy, and new therapeutic strategies are urgently required. This article will focus on how recent discoveries have enhanced our understanding of the molecular pathogenesis of OCCCs, leading to new therapeutic opportunities. These include mutations in ARID1A, which provides a link to endometriosis, upregulation of the phosphatidylinositol 3-kinase/AKT pathway, particularly through mutations of PIK3CA and inactivation of PTEN, and increased activity of pathways involved in angiogenesis. Targeting HER2, apoptotic escape mechanisms and mismatch repair defects offer additional opportunities for treating this enigmatic tumour subtype.     

透明细胞乳头状肾细胞癌临床病理特征分析

目的:探讨透明细胞乳头状肾细胞癌（CCPRCC）的临床及病理学特征。方法:回顾性分析6例CCPRCC的临床特征、组织学特点及免疫表型,并复习相关文献。结果:6例肿瘤均位于肾皮质内,肿瘤边界清晰,有纤维性包膜,切面灰红或灰黄色,部分呈囊性改变。镜下肿瘤呈乳头状、管状、囊性及实性混合性生长,胞浆透明,细胞核远离基底膜,世界卫生组织（World Health Organization,WHO）/国际泌尿病理协会（International Society of Urological Pathology,ISUP)分级为1级或2级。免疫表型:6例肿瘤组织均表达CK7、PAX-8和34βE12,CAIX呈“杯状”或完全膜阳性表达。1例CD10部分阳性,其余5例CD10阴性。所有病例AMACR和TFE3均为阴性。结论:透明细胞乳头状肾细胞癌是一种少见的肾肿瘤,呈惰性生物学行为。形态上应与具有透明细胞和乳头状结构的肾细胞癌鉴别,可借助免疫组织化学和分子遗传学检测予以鉴别。     

卵巢外腹膜浆液性乳头状癌与卵巢浆液性乳头状癌比较分析

目的　探讨卵巢外原发腹膜浆液性乳头状癌 (EPSPC)的临床和治疗特点及预后。方法回顾性分析 12例EPSPC与 4 5例Ⅲ、Ⅳ期卵巢浆液性乳头状癌 (OPSC)的临床和随访资料 ,比较其临床及治疗特点、对一线化疗药物的敏感性及生存时间。结果　EPSPC与OPSC两组的症状、体征、CA12 5水平、无瘤期、复发时间、对一线化疗药物的反应及生存时间差异无统计学意义 ,而EPSPC组的完全缓解率 (2 5 .0 % )与OPSC组 (91.8% )比较 ,显著降低 (P <0 .0 1)。结论　EPSPC与OPSC临床过程类似 ,当治疗手段相同时 ,对一线化疗药物的敏感性及生存时间相近。     

PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, although the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC.     

子宫内膜异位症相关性卵巢透明细胞癌和卵巢子宫内膜样癌的临床病理特征研究

目的 研究子宫内膜异位症(EM)相关性卵巢透明细胞癌(CCC)和卵巢子宫内膜样癌(EC)的临床病理特征.方法 选取CCC和EC患者共167例,根据是否为EM恶变将患者分为EM组(n=84)和非EM组(n=83).比较两组患者的年龄、生育史、EM病史、临床表现、凝血功能、血清CA125水平、超声检查结果、术中情况及术后病理特点.结果 EM组患者的发病年龄、初潮年龄均明显小于非EM组(P﹤0.01),未绝经患者所占比例明显低于非EM组(P﹤0.01);EM组患者的孕次、产次明显低于非EM组(P﹤0.001),不孕症患者所占比例明显高于非EM组(P﹤0.001);EM组中既往有EM病史的患者所占比例高于非EM组(P﹤0.05);临床表现方面,EM组患者的痛经、月经紊乱发生率均明显高于非EM组(P﹤0.01);EM组患者的PT、APTT明显短于非EM组(P﹤0.001);术后,EM组患者的血清CA125水平低于非EM组(P﹤0.05);两组患者超声检查结果比较,差异无统计学意义(P﹥0.05);EM组患者的肿瘤直径明显大于非EM组(P﹤0.001);两组患者的FIGO分期比较,差异有统计学意义(P﹤0.05),其中EM组患者中Ⅰ~Ⅱ期患者所占比例高于非EM组.结论 EM相关性CCC和EC与单纯CCC和EC存在明显不同的临床病理特征,具有确诊年龄及初潮年龄小、绝经比例更高、孕产次更低、既往有EM病史患者所占比例更高、痛经和月经紊乱表现更多、PT和APTT更短、血清CA125水平较低和临床病理分期较早等特点.     

大黄素对人胃癌细胞MKN45增殖抑制作用及其分子机制的探讨

目的:研究大黄素(Emodin)对人胃癌细胞MKN45的作用及探讨其诱导MKN45凋亡的分子机制。方法:用MTT法观察大黄素对MKN45的生长抑制作用;荧光染色法及流式细胞仪分析诱导凋亡作用;蛋白质印迹法检测p53和p21蛋白水平的变化;细胞免疫化学法检测Fas的表达。结果:与对照组相比,大黄素能明显抑制MKN45细胞的生长且呈浓度、时间依赖性,其IC50(48h)为(47.5±0.3)μmol/L;大黄素处理胃癌细胞后,吖啶橙(AO)染色观察示,细胞核内可见浓染致密的颗粒荧光、新月型改变、核固缩或片段化及凋亡小体的形成。流式细胞仪分析显示,大黄素能浓度依赖性诱导MKN45细胞凋亡和G2/M期阻滞。蛋白质印迹法检测显示,随着药物浓度的不断增加,p53和p21WAF1蛋白水平表现出明显增强的趋势;细胞免疫化学方法显示,大黄素处理后的细胞Fas/APO-1表达较对照组明显增多。结论:大黄素对人胃癌细胞MKN45有明显的生长抑制作用,且该作用与p53依赖性诱导凋亡以及Fas表达水平的上调有关。     

透明细胞乳头状肾细胞癌7例报告并文献复习

背景与目的：透明细胞乳头状肾细胞癌是最近发现的一种少见的肾脏上皮源性恶性肿瘤,其生物学行为惰性,预后较好,该研究旨在分析透明细胞乳头状肾细胞癌的临床及病理学特点,与其他亚型鉴别,以免过度治疗。方法：收集7例透明细胞乳头状肾细胞癌病例,应用组织病理学、免疫组织化学法并结合相关文献分析其镜下及临床特点。结果：7例患者肿块均位于肾内,切面灰红或灰黄色,实性或囊实性,镜下肿瘤组织呈腺管状、微囊状或乳头状结构,肿瘤以一种结构为主或多种结构混合存在。细胞质透明,细胞核圆形或卵圆形,世界卫生组织（World Health Organization,WHO）/国际泌尿病理协会（International Society of Urological Pathology,ISUP）细胞核分级为1或2级。免疫表型：7例均表达CK7、CK8、vimentin、PAX-8、CA9和CK34βE12,Ki-67增殖指数为5%~10%,7例均不表达CD117、TFE3和CD10。对本组7例患者随访2个月至4年,均无复发及转移。结论：透明细胞乳头状肾细胞癌是一种少见的低度恶性肿瘤,形态学上与多种具有透明细胞和（或）乳头状细胞的肾癌有重叠,需要借助免疫组织化学进行鉴别。     

超声诊断卵巢透明细胞癌

目的 探讨术前超声诊断卵巢透明细胞癌(ovarian clear cell carcinoma,OCCC)的临床价值.方法 回顾性分析14例经手术病理检查证实的OCCC患者资料,观察OCCC的临床特征及术前超声表现.结果 3例病灶位于双侧卵巢,11例病灶位于单侧卵巢.超声表现为类圆形或类椭圆形肿块,边界清,有包膜;实性...     

Coexisting clear cell adenocarcinoma and squamous cell carcinoma arising from ovarian endometriosis

A case of clear cell adenocarcinoma and squamous cell carcinoma coexisting in the ovary is presented. These two malignancies were adjacent but were not admixed, and ovarian endometriosis was confirmed concurrently. The clear cell adenocarcinoma was contiguous to monolayered glandular cells with cytological and architectural atypia, while squamous metaplasia with cellular atypia was observed adjacent to the squamous cell carcinoma. We concluded that these two malignancies arose independently from ovarian endometriosis. To our knowledge, this is the first report of such a case. Received: April 19, 2000 / Accepted: August 28, 2000     

miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma

High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.     

X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary

Background:

X-chromosome-linked inhibitor of apoptosis (XIAP) is one of the anti-apoptotic proteins leading to chemoresistance in several cancers. The aim of this study is to evaluate the impact of XIAP expression upon ovarian clear cell carcinoma (CCC) that has a platinum-resistant phenotype.

Methods:

Tissue microarrays made from 90 CCC patients were analysed for immunohistochemical expression levels of XIAP, c-Met, p-Akt and Bcl-XL. In addition, CCC cell lines were evaluated whether XIAP silencing could modulate sensitivity to platinum agent in vitro.

Results:

High XIAP expression was observed in 30 (33%) of 90 CCC cases, and was associated with c-Met (<0.01) and Bcl-XL (<0.01) expression. Cases with high XIAP expression had lower response rate to primary platinum-based chemotherapy (10% vs 65%, P=0.02). In stages II–IV tumours, high XIAP expression was related with worse progression-free survival (PFS, P=0.02). Furthermore, high XIAP expression was identified as an independent worse prognostic factor for PFS and overall survival. Finally, downregulation of XIAP using XIAP-specific small interfering RNA increased sensitivity to cisplatin in human cancer cells derived from CCC.

Conclusions:

X-chromosome-linked inhibitor of apoptosis expression was correlated with chemoresistance of primary chemotherapy, and identified as a prognostic marker for CCC. X-chromosome-linked inhibitor of apoptosis could be a candidate for new therapeutic target in CCC.