Muscle differentiation is a crucial process controlling muscle development and homeostasis. Mitochondrial reactive oxygen species (mtROS) rapidly increase and function as critical cell signaling intermediates during the muscle differentiation. However, it has not yet been elucidated how they control myogenic signaling. Autophagy, a lysosome-mediated degradation pathway, is importantly recognized as intracellular remodeling mechanism of cellular organelles during muscle differentiation. Here, we demonstrated that the mtROS stimulated phosphatidylinositol 3 kinase/AKT/mammalian target of rapamycin (mTOR) cascade, and the activated mTORC1 subsequently induced autophagic signaling via phosphorylation of uncoordinated-51-like kinase 1 (ULK1) at serine 317 and upregulation of Atg proteins to prompt muscle differentiation. Treatment with MitoQ or rapamycin impaired both phosphorylation of ULK1 and expression of Atg proteins. Therefore, we propose a novel regulatory paradigm in which mtROS are required to initiate autophagic reconstruction of cellular organization through mTOR activation in muscle differentiation.

Identification of a potential gene signature for improved diagnosis in non-small cell lung cancer (NSCLC) patient is necessary. Here, we aim to establish and validate the prognostic efficacy of a gene set that can predict prognosis and benefits of adjuvant chemotherapy (ACT) in NSCLC patients from various ethnicities. An 8-gene signature was calculated from the gene expression of 181 patients using univariate Cox proportional hazard regression analysis. The prognostic value of the signature was robustly validated in 1,477 patients from five microarray independent data sets and one RNA-seq data set. The 8-gene signature was identified as an independent predictor of patient survival in the presence of clinical parameters in univariate and multivariate analyses [hazard ratio (HR): 2.84, 95% confidence interval CI (1.74-4.65), p=3.06e-05, [HR] 2.62, 95% CI (1.51-4.53), p=0.001], respectively. Subset analysis demonstrated that the 8-gene signature could identify high-risk patients in stage II-III with improved survival from ACT [(HR) 1.47, 95% CI (1.01-2.14), p=0.044]. The 8-gene signature also stratified risk groups in EGFR-mutated and wild-type patients. In conclusion, the 8-gene signature is a strong and independent predictor that can significantly stratify patients into low- and high-risk groups. Our gene signature also has the potential to predict patients in stage II-III that are likely to benefit from ACT.

Patient diagnosis and care would be significantly improved by understanding the mechanisms underlying platinum and taxane resistance in ovarian cancer. Here, we aim to establish a gene signature that can identify molecular pathways/transcription factors involved in ovarian cancer progression, poor clinical outcome, and chemotherapy resistance. To validate the robustness of the gene signature, a meta-analysis approach was applied to 1,020 patients from 7 datasets. A 97-gene signature was identified as an independent predictor of patient survival in association with other clinicopathological factors in univariate [hazard ratio (HR): 3.0, 95% Confidence Interval (CI) 1.66–5.44, p = 2.7E-4] and multivariate [HR: 2.88, 95% CI 1.57–5.2, p = 0.001] analyses. Subset analyses demonstrated that the signature could predict patients who would attain complete or partial remission or no-response to first-line chemotherapy. Pathway analyses revealed that the signature was regulated by HIF1α and TP53 and included nine HIF1α-regulated genes, which were highly expressed in non-responders and partial remission patients than in complete remission patients. We present the 97-gene signature as an accurate prognostic predictor of overall survival and chemoresponse. Our signature also provides information on potential candidate target genes for future treatment efforts in ovarian cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Chemoresistance is a major problem for effective therapy in CRC. Here, we investigated the mechanism by which peptidylprolyl isomerase B (PPIB; cyclophilin B, CypB) regulates chemoresistance in CRC. We found that CypB is a novel wild-type p53 (p53WT)-inducible gene but a negative regulator of p53WT in response to oxaliplatin treatment. Overexpression of CypB shortens the half-life of p53WT and inhibits oxaliplatin-induced apoptosis in CRC cells, whereas knockdown of CypB lengthens the half-life of p53WT and stimulates p53WT-dependent apoptosis. CypB interacts directly with MDM2, and enhances MDM2-dependent p53WT ubiquitination and degradation. Furthermore, we firmly validated, using bioinformatics analyses, that overexpression of CypB is associated with poor prognosis in CRC progression and chemoresistance. Hence, we suggest a novel mechanism of chemoresistance caused by overexpressed CypB, which may help to develop new anti-cancer drugs. We also propose that CypB may be utilized as a predictive biomarker in CRC patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mitochondria play various important roles in energy production, metabolism, and apoptosis. Mitochondrial dysfunction caused by alterations in mitochondrial DNA (mtDNA) can lead to the initiation and progression of cancers and other diseases. These alterations include mutations and copy number variations. Especially, the mutations in D-loop, MT-ND1, and MT-ND5 affect mitochondrial functions and are widely detected in various cancers. Meanwhile, several other mutations have been correlated with muscular and neuronal diseases, especially MT-TL1 is deeply related. These pieces of evidence indicated mtDNA alterations in diseases show potential as a novel therapeutic target. mtDNA repair enzymes are the target for delaying or stalling the mtDNA damage-induced cancer progression and metastasis. Moreover, some mutations reveal a prognosis ability of the drug resistance. Current efforts aim to develop mitochondrial transplantation technique as a direct cure for deregulated mitochondria-associated diseases. This review summarizes the implications of mitochondrial dysfunction in cancers and other pathologies; and discusses the relevance of mitochondria-targeted therapies, along with their contribution as potential biomarkers.