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

Simple Summary LEMT2 was a newly discovered protein-encoding gene with little cancer research and an unclear mechanism. This study aimed to illustrate LETM2 as the crucial oncogene for tumor progression in pancreatic ductal adenocarcinoma (PDAC). We analyzed the expression level and prognostic value of LETM2 in multiple cancers using pan-cancer analysis and found that the LETM2 expression was the most significantly related to the dismal prognosis of PDAC. Immunohistochemical analyses showed that high LETM2 expression was correlated with poor outcomes of PDAC. In in vitro and in vivo experiments, LETM2 knockdown significantly inhibited tumor proliferation and metastasis, while LETM2 overexpression exerted the opposite effects. Then, we suggested that LETM2 may facilitate tumor progression by activating downstream PI3K-Akt signaling pathway in PDAC. In conclusion, the study enhanced our understanding of the LETM2-regulated PI3K-Akt signaling axis served as a prognostic and therapeutic target of 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.

Automated summary

LEMT2, a newly discovered protein-encoding gene, has been found to be significantly associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Knockdown of LEMT2 inhibits tumor proliferation and metastasis, while overexpression of LEMT2 has the opposite effects. LEMT2 may facilitate tumor progression in PDAC by activating the PI3K-Akt signaling pathway.