Alternative splicing has been shown to causally contribute to the epithelial-mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein-protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.
During breast cancer metastasis, the developmental process epithelial–mesenchymal transition (EMT) is abnormally activated. Transcriptional regulatory networks controlling EMT are well-studied; however, alternative RNA splicing also plays a critical regulatory role during this process. A comprehensive understanding of alternative splicing (AS) and the RNA binding proteins (RBPs) that regulate it during EMT and their impact on breast cancer remains largely unknown. In this study, we annotated AS in the breast cancer TCGA data set and identified an AS signature that is capable of distinguishing epithelial and mesenchymal states of the tumors. This AS signature contains 25 AS events, among which nine showed increased exon inclusion and 16 showed exon skipping during EMT. This AS signature accurately assigns the EMT status of cells in the CCLE data set and robustly predicts patient survival. We further developed an effective computational method using bipartite networks to identify RBP-AS networks during EMT. This network analysis revealed the complexity of RBP regulation and nominated previously unknown RBPs that regulate EMT-associated AS events. This study highlights the importance of global AS regulation during EMT in cancer progression and paves the way for further investigation into RNA regulation in EMT and metastasis.
Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition (EMT) is a developmental process that plays an essential role in metazoan embryogenesis. Recent studies have revealed that alternative splicing serves as a fundamental layer of regulation that governs cells to undergo EMT. In this review, we summarize recent findings on the functional impact of alternative splicing in EMT and EMT-associated activities. We then discuss the regulatory mechanisms that control alternative splicing changes during EMT.
Objective: A prospective, multicenter, randomized controlled trial was conducted to explore the short-term effect of a new robotic-assisted total knee arthroplasty (TKA) system, and the clinical and radiographic effectiveness between the robotic-assisted system and conventional TKA were compared and analyzed. Materials and Methods: Overall, 144 patients were randomly divided into two groups, wherein 72 patients underwent TKA using the robotic‑assisted system and 72 underwent conventional TKA. The demographic data and radiographic parameters of the patients were collected. The factors influencing postoperative hip–knee–ankle (HKA) angle deviation were determined by multiple linear regression. Clinical outcomes including postoperative Knee Society score, 10-cm visual analog scale, and range of motion (ROM) and radiographic results including the deviation value of coronal tibial component angle, coronal femoral component angle (CFCA), sagittal tibial component angle, sagittal femoral component angle (SFCA), and HKA angle as well as the rate of outliers in each angle were observed and compared between the two groups. Results: The preoperative demographic data and imaging parameters, including Knee Society score, ROM, sex, surgical side, age, BMI, preoperative HKA angle, preoperative HKA angle deviation, and visual analog scale, showed no significant differences between groups. The robotic‑assisted system group (RAS group) showed a postoperative malalignment of 3.2% for a mechanical axis higher than 3° and the conventional techniques group (CON group) showed a postoperative malalignment of 41.0% for a mechanical axis higher than 3°; the difference was statistically significant (P<0.001). According to the results of multiple linear regression analysis, when the preoperative HKA angle deviation increased by 1°, the postoperative HKA angle deviation increased by 0.134° (β=0.134 min; 95% CI: 0.045–0.222). Therefore, patients were divided into a slight lower extremity alignment deviation group (preoperative HKA angle deviation <6°) and severe lower extremity alignment deviation group (preoperative HKA angle deviation ≥6°). For the patients with preoperatively slight lower extremity alignment deviation, the rate of postoperative HKA angle outlier in the RAS group was better than that in the CON group, and the operation duration in the RAS group was significantly longer than that in the CON group (P<0.05). In the patients with a preoperative HKA angle deviation ≥6°, the rate of postoperative HKA angle and CFCA outliers in the RAS group was better than that in the CON group; the operation duration in the RAS group was significantly longer than that in the CON group, and the HKA angle deviation and CFCA deviation in the RAS group were significantly lower than those in the CON group (P<0.05). No significant difference was observed in other indexes between the two groups (P>0.05). Conclusion: This new robotic-assisted TKA system is safe and effective. The authors found that preoperative HKA angle deviation affects the postoperative HKA angle deviation. The robotic-assisted system has similar results to those reported by the traditional method with regard to restoring the mechanical axis of the leg and improving prosthesis alignment and clinical outcomes in patients with slight lower extremity alignment deviations preoperatively. For patients with severe preoperative lower extremity alignment deviations, the effectiveness in terms of the improvement in mechanical axis of the leg and prosthesis alignment were better with the robotic-assisted system, whereas the effectiveness of clinical outcomes was similar. A larger sample size and longer follow-up period are needed to determine whether the improved mechanical axis of the leg and prosthesis alignment observed with the robotic-assisted system can achieve better long-term radiographic and clinical outcomes.
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