Breast carcinoma with osteoclast-like giant cells (BC-OGC) is a rare morphological variant of invasive breast cancer characterized by scattered benign-appearing giant cells in the stroma. Although these cells are believed to be macrophage-derived, their biological role, polarization state, and clinical significance remain unclear. Recent data suggest that tumor-derived RANKL may drive giant cell formation and influence tumor aggressiveness. A total of 12 BC-OGC cases diagnosed between 2012 and 2024 were retrospectively analyzed, along with 36 matched breast cancer cases without osteoclast-like giant cells (non-BC-OGC). Clinicopathological, immunophenotypic, and stromal features were compared. Immunohistochemistry assessed the expression of macrophage markers (CD68, CD163, CD206) and RANKL. Associations with metastatic outcomes were evaluated. In vitro, the effects of RANKL overexpression and knockdown on breast cancer cell proliferation, migration, and invasion were evaluated using MCF7 cell lines. BC-OGC cases predominantly exhibited the Luminal A-like molecular subtype but showed distinctive loose, vascular-rich stroma compared to controls (p = 0.018). Osteoclast-like giant cells expressed macrophage markers, with widespread CD68 positivity and partial M2 polarization (CD163, CD206). RANKL immunostaining was significantly stronger and more diffuse in BC-OGC than in controls (p = 0.00386), with expression highest in metastatic cases. Metastatic events occurred more frequently in BC-OGC (33.3

Esophageal squamous carcinoma and colorectal adenocarcinoma are both the most common digestive tract tumors in China, and they share certain similarities in genetic susceptibility, major risk factors and molecular mechanisms. However, comparative studies on these two tumors with large sample sizes are still lacking. This study was conducted to analyze the differences between the two tumors in clinicopathological features and tumor-associated protein expression, their impact on survival, and to provide a basis for the identification of molecular markers of early detection and targeted therapy. In this study, 26 tumor-associated proteins were selected from 20,097 patients with esophageal squamous carcinoma and colorectal adenocarcinoma. The chi 2 test was applied to compare the differences between the two tumors in terms of clinicopathological features and protein expression. The Kaplan-Meier survival analysis and Cox regression analysis were used to compare the relationship between the clinicopathological features and protein expression and the survival of patients. Significant differences were found between patients with esophageal squamous carcinoma and those with colorectal adenocarcinoma in gender, age, degree of differentiation, margins, TNM stage, vascular embolism, neurological invasion and family history. In addition, age, lymph node metastasis, TNM stage and degree of differentiation had similar effects on the prognosis of patients with both tumors, and gender had opposite effects on the prognosis of patients with both tumors. Of the 26 tumor-associated proteins examined in 100 and more cases, 19 proteins were differentially expressed in the two tumors. Further Kaplan-Meier survival analysis of these 26 proteins showed that in esophageal squamous carcinoma, CK (P=0.005) and EGFR (P=0.002) and Syn (P=0.002)-positive patients had a poorer prognosis than negative patients, and CK8/18 (P=0.039) and Her-2 (P=0.002) positive patients had a better prognosis than negative patients. In colorectal cancer, Syn (P=0.002) and CK7 (P<0.001) positive patients had poorer prognosis than negative patients, and VEGF positive patients had better prognosis than VEGF negative patients (P=0.003).We further applied multivariate Cox regression analysis to evaluate the effect of survival-related proteins on the prognosis of patients with esophageal squamous carcinoma or colorectal adenocarcinoma, and found that Syn positivity (HR=3.860, 95%CI (1.377-11.144), P=0.013) was an independent risk factor for the prognosis of patients with esophageal squamous carcinoma; in colorectal adenocarcinoma, CK7 positivity (HR=2.446, 95%CI (1.427-4.193), P=0.001) and Syn positivity (HR=3.492, 95%CI (1.377-8.854), P=0.008) were independent risk factors for the prognosis of colorectal adenocarcinoma patients, and VEGF positivity (HR=0.007, 95%CI (0.001-0.337), P=0.013) was an independent protective factor for the prognosis of colorectal adenocarcinoma patients. Syn protein was found to be an independent prognostic factor in both tumors. These important findings provide an important reference for the clinical personalized diagnosis and treatment of the two types of tumors, as well as objective evidence of the intrinsic connection of the two types of tumors, which deepens our understanding of the intrinsic connection between the two types of tumors.

Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12-63 years (median 44). Twenty-eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0-1/10 high-power fields, HPF). A single patient with distant metastasis harboured a solid-predominant tumour showing nuclear grade 2-3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan-TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2-30% of tumour cells), and all were HER2 negative or low (0-1+). Ki-67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6-NTRK3 dual-fusion; 3 NTRK3 break-apart). In the metastatic case, RNA sequencing confirmed canonical ETV6-NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) - RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow-up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6-NTRK3 rearrangement with diffuse pan-TRK/S100 positivity. A solid-predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK-inhibitor therapy in advanced disease.

Background: Breast phyllodes tumor (PT) is a biphasic tumor and constitutes about 0.3% to 1% of all breast tumors. The PT is histologically classified as benign, borderline, and malignant subtypes. Unlike epithelial breast cancers, PT is derived from breast fibroepithelial tissues, and the genomic information of PT subtypes is still limited. Objectives: The objectives were to gain a deeper understanding of genomic changes in the progression of PTs from benign and borderline to malignant. Design: In this study, we used an Affymetrix OncoScan Array to analyze the genome-wide copy number variations (CNVs) and nucleotide point mutations from 3 benign PTs, 3 borderline PTs, and 3 malignant PTs collected from the First Affiliated Hospital of Zhengzhou University. Methods: DNA was extracted from formalin-fixed paraffin-embedded (FFPE) specimens using the TIANamp FFPE DNA Kit. The DNA was profiled for genome-wide CNV using the Affymetrix OncoScan Array and analyzed using the Nexus Express Chromosome Analysis Suite. Results: Our in silico variation analysis indicated copy number loss in Xp11.22 to q22.1 of all benign PTs (χ 2 = 9, P = .0027) and 22q11.23 and Xq23 in all malignant PTs (χ 2 = 12, P = .0005). A copy number gain was observed in 1p13.3 of all borderline PTs (χ 2 = 9, P = .0027) and 7p11.2 of all malignant PTs (χ 2 = 9, P = .0027). We also found consistent loss of heterozygosity (LOH) in 32 loci of benign PTs, 32 loci of borderline PTs, and 23 loci of malignant PTs. Among the 87 LOH, there were 15 overlapping loci across all PT subtypes. We observed missense mutations of NRAS , KRAS , IDH2 , TP53 , and a frameshift deletion in PTEN of sequenced PT samples, irrespective of their subtype. Interestingly, a point mutation in EGFR/EGFR-AS1 was only observed in malignant PTs. Conclusions: Our data suggested that CNV at 7p11.2, 22q11.23, and Xq23 together with a point mutation in EGFR / EGFR-AS1 uniquely presented in malignant PTs may correlate with the progression of PTs.

It has been discovered that Trichorhinophalangeal Syndrome-1 (TRPS1), a novel member of the GATA transcription factor family, participates in both normal physiological processes and the development of numerous diseases. Recently, TRPS1 has been identified as a new biomarker to aid in cancer diagnosis and is very common in breast cancer (BC), especially in triple-negative breast cancer (TNBC). In this review, we discussed the structure and function of TRPS1 in various normal cells, focused on its role in tumorigenesis and tumor development, and summarize the research status of TRPS1 in the occurrence and development of BC. We also analyzed the potential use of TRPS1 in guiding clinically personalized precision treatment and the development of targeted drugs.

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of breast myofibroblastoma. Methods: The clinicopathological data and prognostic information of 15 patients with breast myofibroblastoma diagnosed at the Department of Pathology of the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from 2014 to 2022 were collected. Their clinical characteristics, histological subtypes, immunophenotypes and molecular characteristics were analyzed. Results: There were 12 female and 3 male patients, ranging in age from 18 to 78 years, with a median and average age of 52 years. There were 6 cases in the left breast and 9 cases in the right breast, including 12 cases in outer upper quadrant, 2 cases in inner upper quadrant and 1 case in outer lower quadrant. Most of the cases showed a well-defined nodule grossly, including pushing growth under the microscope in 13 cases, being completely separated from the surrounding breast tissue in 1 case, and infiltrating growth in 1 case. Among them, 12 cases were classic subtype and composed of occasional spindle cells with varying intervals of collagen fiber bundles; eight cases had a small amount of fat; one case had focal cartilage differentiation; one case was epithelioid subtype, in which epithelioid tumor cells were scattered in single filing or small clusters; one case was schwannoma-like subtype, and the tumor cells were arranged in a significant palisade shape, resembling schwannoma, and one case was invasive leiomyoma-like subtype, in which the tumor cells had eosinophilic cytoplasm and were arranged in bundles, and infiltrating into the surrounding mammary lobules like leiomyoma. Immunohistochemical studies showed that the tumor cells expressed desmin (14/15) and CD34 (14/15), as well as ER (15/15) and PR (15/15). Three cases with histologic subtypes of epithelioid subtype, schwannoma-like subtype and infiltrating leiomyoma-like subtype showed RB1 negative immunohistochemistry. Then FISH was performed to detect RB1/13q14 gene deletion, and identified RB1 gene deletion in all three cases. Fifteen cases were followed up for 2-100 months, and no recurrence was noted. Conclusions: Myofibroblastoma is a rare benign mesenchymal tumor of the breast. In addition to the classic type, there are many histological variants, among which the epithelioid subtype is easily confused with invasive lobular carcinoma. The schwannoma-like subtype is similar to schwannoma, while the invasive subtype is easily misdiagnosed as fibromatosis-like or spindle cell metaplastic carcinoma. Therefore, it is important to recognize the various histological subtypes and clinicopathological features of the tumor for making correct pathological diagnosis and rational clinical treatment.

目的 探讨儿童和青少年腺泡状软组织肉瘤(alveolar soft part sarcoma,ASPS)的临床病理学特征.方法 回顾性分析2012年1月～2020年12月郑州大学第一附属医院收治的22例儿童和青少年ASPS的临床、影像学特征、组织病理学特征和预后情况.结果 22例儿童和青少年ASPS中男性12例,女性10例,中位年龄11.4岁(范围1.4～18岁),中位肿瘤最大径为4.7 cm,原发肿瘤均位于肌内或筋膜下,以下肢多见.临床通常表现为无痛性增长的肿块.18例患者在增强CT或MR图像上均出现对比度增强.镜下见肿瘤细胞由薄壁窦隙样血管分割成巢状、腺泡状,部分病例呈实性、片状生长;肿瘤细胞胞质红染或透亮,胞核呈圆形、卵圆形,可见明显核仁,核分裂象少见,有血管内瘤栓.最显著的免疫组化和基因组学特征:TFE-3强阳性或基因断裂.22例患者平均随访时间44.7个月(5～108个月),其中8例带瘤生存,13例无瘤生存,1例死亡,5年生存率为95.2％.结论 ASPS特征性的影像学、组织学和免疫表型特征有助于早期诊断和鉴别诊断;儿童和青少年APSP患者预后较好,5年生存率较高.

Abstract Background Alveolar soft-part sarcoma (ASPS) is a rare soft tissue sarcoma subtype, occurring mainly in young people, with poor prognosis. Materials and methods We conducted a retrospective analysis of localized or metastatic ASPS patients admitted to the First Affiliated Hospital of Zhengzhou University (China) from 2012 to 2020, focusing on treatment and prognosis. Results The median age at diagnosis was 24 years (range: 1.4–78 years). Women (n = 29, 58%), especially those aged <30 years, dominated this series. The most common metastasis site was lung. Thirty-one (62%) patients developed lung metastasis (localized: n = 9 [18%]; metastatic: n = 22 [44%]). Only a tumor maximum diameter ≥ 5 cm was associated with a high lung metastasis rate (p = 0.039). The mean follow-up time was 37.5 months (1–108 months), and the 5-year overall survival (OS) rate was 84.7%. Univariate analysis indicated that distant metastasis observed at the initial visit and incomplete resection of the primary tumor were associated with poor OS. For localized cases, neither surgery plus radiotherapy (p = 0.486) nor surgery plus chemotherapy (p = 0.536) improved progression-free survival compared to surgery alone. Among the metastatic cases, the disease control rate (PR + SD) was higher for targeted therapy (60%) and combined immunosuppressive therapy (100%) than for conventional cytotoxic chemotherapy (26%). Conclusions Postoperative adjuvant radiotherapy and chemotherapy do not provide good local control for patients with localized disease. Although there is no standard treatment strategy for patients with advanced or metastatic disease, they can benefit from targeted therapy and/or immunosuppressive therapy.

Estrogen receptor α (ERα) is the most common clinical marker used for breast cancer prognosis and the classification of breast cancer subtypes. Clinically, patients with estrogen receptor-positive breast cancer can receive endocrine therapy. However, resistance to endocrine therapy has become an urgent clinical problem. A large number of previous studies have proven that posttranslational modification of the estrogen receptor is significantly related to endocrine therapy resistance. RNF2 is a member of the RING finger protein family that functions as an E3 ubiquitin ligase. Several studies have clarified that RNF2 is a critical regulator of ERα transcriptional regulation. In our current study, we identified RNF2 as an important posttranslational modification regulator of the estrogen receptor. RNF2 depletion inhibited breast cancer cell progression and ERα signaling activity. TCGA data analysis indicated that RNF2 was elevated in breast malignancies, while RNF2 depletion could drastically inhibit estrogen response gene expression on a whole-genome scale. TCGA data analysis revealed that RNF2 was positively correlated with ERα target gene expression. Further mechanistic studies showed that RNF2 was mainly localized in the nucleus and associated with ERα. The association increased ERα stability by inhibiting ERα K48-linked polyubiquitination. In conclusion, our study implicates nongenomic regulation by RNF2 on ERα protein stability and suggests that targeting RNF2 could be a promising strategy for breast cancer treatments.

目的 分析ZC3H13在透明细胞肾细胞癌(ccRCC)中的表达及预后意义.方法 利用Ualcan和GEPIA数据库分析并验证ZC3H13 mRNA在ccRCC中的表达及其与临床病理指标和生存期的关系,对ZC3H13基因进行共表达分析及相关性分析.利用人类蛋白质图谱(HPA)数据库中的细胞系及免疫组化结果分析ZC3H13蛋白在ccRCC中的定位及表达情况.利用STRING在线分析以ZC3H13为中心相关蛋白之间的相互作用.结果 Ualcan数据库结果显示,在ccRCC、乳头状肾细胞癌(PRCC)、嫌色细胞肾细胞癌(CRCC)中,ZC3H13 mRNA表达水平均下调(P<0,05).GEPIA数据库结果显示,相比于正常肾组织,ZC3H13 mRNA在ccRCC、PRCC、CRCC这3种亚型肾细胞癌中表达水平均下调(P<0,05).Ualcan数据库结果显示:Ⅰ期ccRCC患者ZC3H13 mRNA表达水平高于Ⅲ期者(P<0,05);与ccA型比较,ccB型ccRCC患者的ZC3H13 mRNA表达水平较低(P<0,05);ccRCC患者的组织学分级与ZC3H13 mRNA的表达水平有关,相比于低组织学分级患者,具有高组织学分级的患者ZC3H13 mRNA的表达水平更低(P<0,05).在GEPIA数据库中,随着ccRCC肿瘤分期的升高,ZC3H13 mRNA的表达量逐渐下降(P<0,05).Ualcan数据库挖掘性分析发现,在ccRCC中,与ZC3H13 mRNA高表达组比较,ZC3H13 mRNA低表达组生存期较短(P<0,05).GEPIA验证性分析发现,在ccRCC中,与ZC3H13 mRNA高表达组比较,ZC3H13 mRNA低表达组的总生存期和无瘤生存期下降(P<0,05).HPA数据库结果显示,在A-431肿瘤细胞系中,ZC3H13主要定位于核膜和肌动蛋白丝.利用免疫组化抗体分析显示,ZC3H13蛋白主要表现为细胞核着色,部分胞质轻微着色.ZC3H13与VHL、PBRM1、mTOR、HIF-1α等ccRCC多种关键基因呈正相关(P<0,05).STRING在线分析显示,ZC3H13与WTAP、POLR2B、KIAA1429等基因共同参与RNA修饰与代谢、RNA甲基化等生物学过程.结论 ZC3H13在ccRCC中低表达,与肿瘤恶性生物学行为和不良预后相关.ZC3H13与VHL、PBRM1、mTOR、HIF-1α等ccRCC发生、发展及预后进程中的重要基因存在一定联系,有望成为评估ccRCC预后和指导治疗的新型分子标志物.

Background: The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. Humans who inherit mutant TP53 alleles develop a wide range of early onset cancers, a disorder called Li-Fraumeni Syndrome (LFS). Trp53-deficient mice recapitulate most but not all of the cancer phenotypes observed in TP53-deficient human cancers, indicating that new animal models may complement current mouse models and better inform on human disease development. Materials and Methods: The recent application of CRISPR/Cas9 genetic engineering technology has permitted the emergence of golden Syrian hamsters as genetic models for wide range of diseases, including cancer. Here, the first cancer phenotype of TP53 knockout golden Syrian hamsters is described. Results: Hamsters that are homozygous for TP53 mutations become moribund on average ~ 139 days of age, while hamsters that are heterozygous become moribund at ~ 286 days. TP53 homozygous knockout hamsters develop a wide range of cancers, often synchronous and metastatic to multiple tissues, including lymphomas, several sarcomas, especially hemangiosarcomas, myeloid leukemias and several carcinomas. TP53 heterozygous mutants develop a more restricted tumor spectrum, primarily lymphomas. Conclusions: Overall, hamsters may provide insights into how TP53 deficiency leads to cancer in humans and can become a new model to test novel therapies.

N6-Methyladenosine (m6A) refers to the methylation modification occurring at the nitrogen-6 position of adenosine. Many human physiological processes such as modulation of spermatogenesis are caused by m6A RNA modifications. However, the relationship between m6A RNA methylation regulators and kidney renal clear cell carcinoma (KIRC) remains rarely investigated. This work aimed to explore the influence of m6A RNA methylation regulators in KIRC. We examined abnormally expressed m6A RNA methylation regulators among different clinicopathological features of KIRC. We recognized three subgroups (KIRC1, KIRC2, and KIRC3) with significant differences in overall survival through consensus clustering of m6A RNA methylation regulators. Surprisingly, KIRC2 displayed elevated immune activity, but high proportions of immune-inhibitory cells (Tregs and myeloid-derived suppressor cell) based on single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT analysis. Moreover, the KIRC2 subgroup had the lowest tumor mutation burden levels and the highest expression levels of 80% (12/15) of co-inhibitory molecules. Next, correlation analysis indicated that RBM15B expression was negatively correlated with multiple immune signatures, which was verified by ssGSEA and CIBERSORT analyses. Multiple immune-related and cancer-related pathways were enriched in the group with high RBM15B expression. Furthermore, a four-m6A RNA methylation regulator-based risk signature was constructed based on an ArrayExpress (E-MTAB-3267) dataset and confirmed in the The Cancer Genome Atlas (TCGA) testing cohort. In conclusion, our study successfully classified TCGA samples into three subgroups with different immune signatures, and suggested that the worse prognosis of KIRC2 is probably mediated by immune evasion. These findings will facilitate personalized immunotherapy in patients with KIRC. In addition, the risk score system was revealed as an independent prognostic marker that can predict survival in KIRC patients.

目的:探讨肾上腺腺瘤样瘤的临床病理特征、免疫表型、鉴别诊断及预后。方法:对10例肾上腺腺瘤样瘤的临床表现、影像学、组织学特征和免疫表型进行观察分析并复习相关文献。结果:肾上腺腺瘤样瘤与生殖系统的腺瘤样瘤组织学形态相似，部分病例可见包膜，多数呈浸润性生长，与周围分界不清，可呈腺管样、管囊状、血管瘤样、小梁状及实性排列，常见印戒细胞样细胞；个别病例出现不典型的细胞形态。免疫表型：广谱细胞角蛋白（CKpan，AE1/AE3）、波形蛋白、CK5/6、calretinin、WT1和D2-40均呈阳性，CD34、癌胚抗原和ERG均阴性，Ki-67阳性指数1%~5%。肾上腺腺瘤样瘤的临床及影像学无特异表现。经FISH检测均不存在p16基因缺失。结论:肾上腺腺瘤样瘤发病罕见，确诊依靠病理诊断，免疫组织化学可帮助鉴别诊断减少误诊。

回顾性分析我院2002年9月至2017年8月诊治的6例颈内静脉瘤患者的临床资料。2例囊状瘤体内合并血栓形成，行瘤体部分切除加侧壁吻合术；1例梭状瘤体保守治疗过程中直径进行性增大，行瘤体切除加颈内静脉结扎术。3例患者接受了保守治疗，1例2岁患者保守治疗过程中颈内静脉恢复正常，另2例保守治疗过程中未发生相关并发症。我们认为对于颈内静脉瘤有症状、变大或影响美观的病例必要时可行手术治疗。

Long non-coding RNAs (lncRNAs) are non-protein-coding RNAs longer than 200 nucleotides. Accumulating evidence demonstrates that lncRNA is a potential biomarker for cancer diagnosis and prognosis. However, there are no prognostic biomarkers and lncRNA models for multiple myeloma (MM). Hence, it is necessary to screen novel lncRNA that can potentially participate in the initiation and progression of MM and consequently construct a risk score system for the disease. Raw microarray datasets were obtained from the Gene Expression Omnibus website. Weighted gene co-expression network analysis and principal component analysis identified 12 lncRNAs of interest. Then, univariate, least absolute shrinkage and selection operator Cox regression and multivariate Cox hazard regression analysis identified two lncRNAs (LINC00996 and LINC00525) that were formulated to construct a risk score system to predict survival. Receiver operating characteristic analysis certificated the superior performance in predicting 3-year overall survival (area under the curve = 0.829). The similar prognostic values of the two-lncRNA signature were also observed in the tested The Cancer Genome Atlas dataset. Furthermore, two other lncRNAs (LINC00324 and LINC01128) were differentially expressed between CD138+ plasma cells from normal donors and MM patients and were verified to be associated with cancer stage in the Gene Expression Omnibus dataset. A lncRNA-mediated competing endogenous RNA network, including 2 lncRNAs, 12 mitochondrial RNAs, and 103 target messenger RNAs, was constructed. In conclusion, we developed a two-lncRNA expression signature to predict the prognosis of MM and constructed a key lncRNA-based competing endogenous RNA network in MM. These lncRNAs were associated with survival and are probably involved in the occurrence and progression of MM.

TRAF4 plays an important role in the development and progression of breast cancer, but its impact on chemotherapy resistance is as yet, however, poorly understood. Western blotting, immunoprecipitation, and immunofluorescence staining were used to identify and verify that TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation. Cell proliferation analysis and Flow cytometry analysis were utilized to detect TRAF4′s function on the growth-inhibitory effect of etoposide. Immunohistochemistry was used to detect the expression of TRAF4, SIAH1, and β-catenin. Statistical analysis was used to analyze the relationships between them with clinical parameters and curative effect of chemotherapy pathologically. Our results suggested that TRAF4 prevents SIAH1-mediated β-catenin degradation. TRAF4 was a novel substrate of SIAH1 and the TRAF domain of TRAF4 was critical for binding to SIAH1. TRAF4 reduced the growth-inhibitory effect of etoposide via reducing the number of S-phase cells and suppressing cell apoptosis. Concordantly, we found that breast cancer patients with a low-TRAF4 expression benefited most from chemotherapy, who had higher tumor volume reduction rate and better pathological response, while, the high-TRAF4 expression group had lower tumor volume reduction rate and poor pathological response. TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated β-catenin degradation, which explains the protective effect of TRAF4 on β-catenin during cell stress and links TRAF4 to chemotherapy resistance in tumors. These findings implicated a novel pathway for the oncogenic function of TRAF4.

The Guanylate binding proteins (GBPs) are a family of large GTPases and the most studied GBP family member is the guanylate binding protein 1 (GBP1). Earlier studies revealed that GBP1 expression was inflammatory cytokines-inducible, and most of the studies focused on inflammation diseases. Increasing number of cancer studies began to reveal its biological role in cancers recently, although with contradictory findings in literature. It was discovered from our earlier prostate cancer cell line models studies that when prostate cancer cells treated with either ethidium bromide or a cell cycle inhibitor flavopiridol for a long-term, the treatment-survived tumor cells experienced metabolic reprogramming toward Warburg effect pathways with greater aggressive features, and one common finding from these cells was the upregulation of GBP1. In this study, possible role of GBP1 in two independent prostate cancer lines by application of CRISR/Cas9 gene knockout (KO) technology was investigated. The GBP1 gene KO DU145 and PC3 prostate cancer cells were significantly less aggressive in vitro, with less proliferation, migration, wound healing, and colony formation capabilities, in addition to a significantly lower level of mitochondrial oxidative phosphorylation and glycolysis. At the same time, such GBP1 KO cells were significantly more sensitive to chemotherapeutic reagents. Xenograft experiments verified a significantly slower tumor growth of the GBP1 KO cells in nude mouse model. Furthermore, GBP1 protein expression in clinical prostate cancer sample revealed its aggressive clinical feature correlation and shorter overall survival association. Collectively, our results indicate a pro-survival or oncogenic role of GBP1 in prostate cancer.