<p>Leucine Zipper-EF-Hand Containing Transmembrane Protein 1 Is a Potential Prognostic Biomarker and Promotes Cell Progression in Prostate Cancer</p>

Abstract

The leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial protein that has been associated with the occurrence and development of malignant tumors. Previous studies have shown that LETM1 expression is increased in several types of human cancer and is associated with a poor clinical outcome. However, the role of LETM1 in prostate cancer (PCa) has not yet been determined. In this study, we investigated the clinicopathological significance of LETM1 expression and its role in PCa progression. Methods: We assessed the expression of LETM1 and genes related to cancer stemness, epithelial-mesenchymal transition (EMT), cell cycle, and PI3K/Akt signaling in 133 paraffinembedded PCa tissue samples and cancer cells by using immunohistochemistry, immunofluorescence, and Western blotting. Results: LETM1 expression was significantly increased in PCa, and it was positively correlated with Gleason score, pathologic tumor (pT) stage, clinical stage, and high microvessel density. Survival analysis showed that patients with PCa with a high level of LETM1 expression exhibited a low overall survival. Cox regression analysis indicated that LETM1 is an independent poor prognostic PCa factor. Additionally, the expression of LETM1 was correlated with cancer cell stemness-associated genes, EMT-related genes, cell cycle regulatory genes, and PI3K/Akt signaling gene expression in PCa. Furthermore, knocking down LETM1 expression down-regulated the expression of stemness-related proteins, while inhibiting tumor spheroid formation, EMT-like changes, cell proliferation, migration, and invasion in PCa cells. Importantly, the PI3K inhibitor LY294002 strongly inhibited the expression of LETM1, pPI3K-p85, and pAkt (Thr308, Ser473) in PCa cells. Conclusion: These results indicate that LETM1 expression is associated with cancer cell stemness, promotes EMT-like changes and cell proliferation and is a potential prognostic biomarker for PCa.

LETM1: A Single Entity With Diverse Impact on Mitochondrial Metabolism and Cellular Signaling

“…In thyroid, prostate, ovarian, and gastric cancers, LETM1 overexpression is correlated with increased cell survival via enhanced Akt signaling (Lee et al, 2016;Piao et al, 2020;Wang et al, 2020;Zhang et al, 2020). This is further corroborated by the observation in prostate cancer cells, that the PI3K inhibitor LY294002, which stopped the migration and invasion of tumor cells, also caused the downregulation of LETM1 (Piao et al, 2020). This suggests that LETM1 may mediate Akt signaling through its interaction with the Akt inhibitor, CTMP.…”

“…LETM1-mediated regulation of mitochondrial biogenesis, metabolism, and cell survival signaling has provided impetus to investigate LETM1 activity in various human cancers ( Dimmer et al, 2008 ; Piao et al, 2009a ; Li et al, 2015 ). Multiple human malignancies, including breast, colon, esophagus, lung, ovary, rectum, stomach, and uterine cervix, report high LETM1-expression profile correlating with poor prognosis, low survival rates, upregulation of cancer stemness genes, and enhanced angiogenesis ( Piao et al, 2009a , 2019a , b , 2020 ; Li et al, 2015 , 2020 ; Wang et al, 2015 , 2020 ; Huang et al, 2017a ; Yang et al, 2018 ). In thyroid, prostate, ovarian, and gastric cancers, LETM1 overexpression is correlated with increased cell survival via enhanced Akt signaling ( Lee et al, 2016 ; Piao et al, 2020 ; Wang et al, 2020 ; Zhang et al, 2020 ).…”

“…Multiple human malignancies, including breast, colon, esophagus, lung, ovary, rectum, stomach, and uterine cervix, report high LETM1-expression profile correlating with poor prognosis, low survival rates, upregulation of cancer stemness genes, and enhanced angiogenesis ( Piao et al, 2009a , 2019a , b , 2020 ; Li et al, 2015 , 2020 ; Wang et al, 2015 , 2020 ; Huang et al, 2017a ; Yang et al, 2018 ). In thyroid, prostate, ovarian, and gastric cancers, LETM1 overexpression is correlated with increased cell survival via enhanced Akt signaling ( Lee et al, 2016 ; Piao et al, 2020 ; Wang et al, 2020 ; Zhang et al, 2020 ). This is further corroborated by the observation in prostate cancer cells, that the PI3K inhibitor LY294002, which stopped the migration and invasion of tumor cells, also caused the downregulation of LETM1 ( Piao et al, 2020 ).…”

“…AMPK inhibition would lead to deregulation of the normal progression of the cell cycle. Accordingly, LETM1-KD reduced the expression of cancer stemness-related genes, increased AMPK activation, arrested cell cycle, lowered the number and size of tumor spheroids, and markedly inhibited cell proliferation ( Che et al, 2020 ; Li et al, 2020 ; Piao et al, 2020 ).…”

Picroside II Improves Severe Acute Pancreatitis-Induced Hepatocellular Injury in Rats by Affecting JAK2/STAT3 Phosphorylation Signaling

“…The expression levels of target protein were analyzed using ImageJ software. According to a previous report [ 22 ], IHC scores were measured using the following standard: score 1, weak staining in <50% or moderate staining in <20% of all cells; score 2, weak staining in ≧50%, moderate staining in 20-50% or strong staining in <20% of all cells; and score 3, moderate staining in ≧50% or strong staining in ≧20% of all cells.…”