Fbw7 Inhibits the Progression of Activated B-Cell Like Diffuse Large B-Cell Lymphoma by Targeting the Positive Feedback Loop of the LDHA/lactate/miR-223 Axis.

Background: F-box and WD repeat domain-containing 7 (Fbw7) is well known as a tumor suppressor and ubiquitin ligase which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 promotes apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. This study aimed to identify the mechanism of Fbw7-mediated aerobic glycolysis reprogramming in DLBCL. Methods: Expression levels of Fbw7 and Lactate Dehydrogenase A (LDHA) in human DLBCL samples were evaluated by immunohistochemistry. Crosstalk between Fbw7 and LDHA signaling was analyzed by co-immunoprecipitation, ubiquitination assay, western blotting and mRNA quanlitative analyses. In vitro and in vivo experiments were used to assess the effect of the Fbw7-mediated LDHA/lactate/miR-223 axis on DLBCL cells growth. Results: Fbw7 could interact with LDHA to trigger its ubiquitination and degradation. Inversely, lactate negatively regulated Fbw7 via trigging the expression of miR-223, which targeted Fbw7 3'-UTR to inhibit its expression. In vivo and in vitro experiments revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA's ubiquitination. Conclusions: We demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related aerobic glycolysis reprogramming in DLBCL. Our study uncovers a negative functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition.

A LETM2-Regulated PI3K-Akt Signaling Axis Reveals a Prognostic and Therapeutic Target in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highest mortalities malignant tumors, which is characterized by difficult diagnosis, rapid progression and high recurrence rate. Nevertheless, PDAC responds poorly to conventional therapies, which highlights the urgency to identify novel prognostic and therapeutic targets. LEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. Thus, this study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in PDAC. In this study, we analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis. The analyses based on the TCGA-GTEx dataset indicated that the LETM2 expression was obviously elevated in several cancers, and it was the most significantly related to the dismal prognosis of PDAC. Subsequently, we demonstrated the functional role and mechanism of LETM2 by clinical sample evaluation, and in in vitro and in vivo experiments. Immunohistochemical analyses showed that high expression of LETM2 was correlated with poor outcomes of PDAC. Moreover, we demonstrated that LETM2 knockdown significantly inhibited tumor proliferation and metastasis, and promoted cell apoptosis, while LETM2 overexpression exerted the opposite effects. Finally, the impairment caused by LETM2-knockdown could be recovered via excitation of the PI3k-Akt pathway in vitro and in vivo animal models, which suggested that LETM2 could activate the downstream PI3K-Akt pathway to participate in PDAC progression. In conclusion, the study enhanced our understanding of LETM2 as an oncogene hallmark of PDAC. LETM2 may facilitate tumor progression by activating the PI3K-Akt signaling pathway, which provides potential targets for the diagnosis, treatment, and prognosis of pancreatic cancer.