Elongin B promotes breast cancer progression by ubiquitinating tumor suppressor p14/ARF.

Elongin B (ELOB), a pivotal element in the ELOB/c-Cullin2/5-SOCS-box E3 ubiquitin-protein ligase complex, plays a significant role in catalyzing the ubiquitination and subsequent degradation of a broad spectrum of target proteins. Notably, it is documented to facilitate these processes. However, the regulatory role of ELOB in breast cancer remains ambiguous. In this study, through bio-informatic analysis of The Cancer Genome Atlas and Fudan University Shanghai Cancer Center database, we demonstrated that ELOB was over-expressed in breast cancer tissues and was related to unfavorable prognosis. Additionally, pathway enrichment analysis illustrated that high expression of ELOB was associated with multiple cancer promoting pathways, like cell cycle, DNA replication, proteasome and PI3K - Akt signaling pathway, indicating ELOB as a potential anticancer target. Then, we confirmed that both in vivo and in vitro, the proliferation of breast cancer cells could be significantly suppressed by the down-regulation of ELOB. Mechanically, immunoprecipitation and in vivo ubiquitination assays prompted that, as the core element of Cullin2-RBX1-ELOB E3 ligase (CRL2) complex, ELOB regulated the ubiquitination and the subsequent degradation of oncoprotein p14/ARF. Moreover, the anticancer efficacy of erasing ELOB could be rescued by simultaneous knockdown of p14/ARF. Finally, through analyzing breast cancer tissue microarrays and western blot of patient samples, we demonstrated that the expression of ELOB in tumor tissues was elevated in compared to adjacent normal tissues. In conclusion, ELOB is identified to be a promising innovative target for the drug development of breast cancer by promoting the ubiquitination and degradation of oncoprotein p14/ARF.

Survival nomogram for patients with de novo metastatic breast cancer based on the SEER database and an external validation cohort.

Background: On average, 5-10% of patients are diagnosed with metastatic breast cancer (MBC) at the initial diagnosis. This study aimed to develop a nomogram to predict the overall survival (OS) in these patients. Methods: The nomogram was based on a retrospective study of 9435 patients with de novo MBC from the Surveillance, Epidemiology, and End Results (SEER) database. The predictive accuracy and discriminative ability of the nomogram were determined using the concordance index (C-index), area under the time-dependent receiver operating characteristic curve (AUC), and calibration curve. Decision curve analysis (DCA) was employed to evaluate the benefits and advantages of our new predicting model over the 8th edition of the American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) staging system. The results were validated in a retrospective study of 103 patients with de novo MBC from January 2013 to June 2022 at an institution in northwest China. Results: Multivariate analysis of the primary cohort revealed that independent factors for survival were age at diagnosis, pathological type, histological grade, T stage, N stage, molecular subtype, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery, chemotherapy, and radiotherapy. The nomogram achieved a C-index of 0.688 (95% confidence interval [CI], 0.682-0.694) in the training cohort and 0.875 (95% CI, 0.816-0.934) in the validation cohort. The AUC of the nomograms indicated good specificity and sensitivity in the training and validation cohorts, respectively. Calibration curves showed favorable consistency between the predicted and actual survival probabilities. Additionally, the DCA curve produced higher net gains than by the AJCC-TNM staging system. Finally, risk stratification can accurately identify groups of patients with de novo MBC at different risk levels. Conclusions: The nomogram showed favorable predictive and discriminative abilities for OS in patients with de novo MBC. Other populations from different countries or prospective studies are needed to further validate the nomogram.

Role of kinesin family member 14 in disease monitoring and prognosis in patients with gastrointestinal cancer.

Kinesin family member 14 (KIF14) is not only involved in numerous essential biological activities, such as cytokinesis and myelination, but also regulates several malignant behaviors and progression of cancer. However, its role in gastrointestinal cancer is rarely reported. Therefore, the present study aimed to investigate the association of KIF14 expression with disease-free survival (DFS) and overall survival (OS) times in patients with gastrointestinal cancer. A total of 101 patients with gastrointestinal cancer (36 patients with gastric cancer and 65 patients with colorectal cancer) were retrospectively reviewed, and their cancer samples were collected to detect the protein and mRNA expression levels of KIF14 using immunohistochemistry and reverse transcription-quantitative PCR, respectively. KIF14 protein expression was increased in cancer tissues compared with adjacent tissues (all P<0.001). The protein expression levels of KIF14 were positively associated with T stage (P<0.001), distant metastases (P=0.007) and TNM stage (P<0.001), while KIF14 mRNA expression was positively associated with T stage (P<0.001), lymph node metastasis (P=0.004), distant metastases (P=0.001) and TNM stage (P<0.001). High protein and mRNA expression levels of KIF14 were associated with worse DFS (P<0.001) and OS (P=0.016) times. In addition, high KIF14 protein expression independently predicted unfavorable DFS times (P=0.007). Subgroup analysis revealed that in patients with gastric cancer, KIF14 expression was associated with DFS and OS times, while in patients with colorectal cancer, KIF14 expression was only associated with DFS time, but not with OS time. In conclusion, KIF14 expression was not only associated with advanced pathological differentiation and TNM stage but was also associated with poor survival time in patients with gastrointestinal cancer. These results indicate the potential of KIF14 as a biomarker for gastrointestinal cancer prognosis.