DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells

Wang, Sheng-Fan; Huang, Kuo Chin; Tseng, Wei Chuan; Lo, Jeng‐Fan; Li, Anna Fen Yau; Fang, Wen Liang; Chen, Chian Feng; Yeh, Tien Shun; Chang, Yuh Lih; Chou, Yueh Ching; Hung, Hung Hsu

doi:10.3390/cancers12113463

Cited by 20 publications

(51 citation statements)

References 80 publications

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“…Tid1 maintains and regulates the normal mitochondrial function and ROS homeostasis [ 21 , 24 ]. During tumorigenesis, downregulation of Tid1 can cause abnormal ROS, which can be counteracted by the antioxidant transcriptional factor, Nrf2.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, we reported that the HNSCC patients with higher expression of Tid1 have better overall survival [ 19 , 20 ]. Most recently, we also discovered that Tid1 can function as a tumor suppressor in gastric cancer progression [ 21 ]. It has been reported that Tid1 plays an important role to maintain mitochondrial DNA [ 21 ], membrane potential [ 22 ], and cristae structure [ 23 ], and to modulate the intracellular reactive oxygen species (ROS) [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, we also discovered that Tid1 can function as a tumor suppressor in gastric cancer progression [ 21 ]. It has been reported that Tid1 plays an important role to maintain mitochondrial DNA [ 21 ], membrane potential [ 22 ], and cristae structure [ 23 ], and to modulate the intracellular reactive oxygen species (ROS) [ 24 ]. The Warburg effect is a signature of carcinogenesis, in that mitochondrial dysfunction plus higher intracellular reactive oxygen species (ROS) are associated with it [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence

Chen

Huang

Teo³

et al. 2021

Cancers

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Tid1, a mitochondrial co-chaperone protein, acts as a tumor suppressor in various cancer types. However, the role of Tid1 in hepatocellular carcinoma (HCC) remains unclear. First, we found that a low endogenous Tid1 protein level was observed in poorly differentiated HCC cell lines. Further, upregulation/downregulation of Tid1 abrogated/promoted the malignancy of human HCC cell lines, respectively. Interestingly, Tid1 negatively modulated the protein level of Nrf2. Tissue assays from 210 surgically resected HCC patients were examined by immunohistochemistry (IHC) analyses. The protein levels of Tid1 in the normal and tumor part of liver tissues were correlated with the clinical outcome of the 210 HCC cases. In multivariate analysis, we discovered that tumor size > 5 cm, multiple tumors, presence of vascular invasion, low Tid1 expression in the non-tumor part, and high Nrf2 expression in the non-tumor part were significant factors associated with worse recurrence-free survival (RFS). A scoring system by integrating the five clinical and pathological factors predicts the RFS among HCC patients after surgical resection. Together, Tid1, serving as a tumor suppressor, has a prognostic role for surgically resected HCC to predict RFS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence

Chen

Huang

Teo³

et al. 2021

Cancers

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“…This has been well documented in the case of galectin-7/Bcl-2 interactions [52]. Galectin-7 is also targeted by Tidf1, which represses the oncogenic role of galectin-7 by promoting its degradation [49]. Whether de novo expression of Tidf1 represses galectin-7-induced MMP-9 expression is an interesting possibility that has not, to our knowledge, been studied.…”

Section: How Does Galectin-7 Induce Mmp-9?mentioning

confidence: 91%

“…It was first reported in an experimental lymphoma mouse model, in which the expression of galectin-7 by lymphoma cells was shown to increase the aggressive behavior of lymphoma cells by inducing MMP-9 [27]. We and others have since shown that galectin-7 can induce MMP-9 in breast cancer, ovarian cancer, head and neck cancer, cervical and oral squamous cell carcinomas and, more recently, gastric cancer cells [44][45][46][47][48][49]. In some cases, this association between galectin-7 and MMP-9 was found to be specific, as no such association was found between MMP-9 and galectin-1 or galectin-3 [44,45].…”

Section: De Novo Expression Of Galectin-7 By Mutated P53mentioning

confidence: 99%

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

St‐Pierre

2021

Biomolecules

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It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer.

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Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism

Fann,

Teo,

Lee

et al. 2024

J cachexia sarcopenia muscle

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BackgroundSarcopenic obesity is characterized by excess fat mass and diminished muscular mass/function. DNAJA3, a mitochondrial co‐chaperone protein, plays a crucial role in skeletal muscle development. GMI, an immunomodulatory protein, promotes myogenic differentiation through DNAJA3 activation. This study aims to elucidate the physiological effects of muscular Dnaja3 haploinsufficiency on mitochondrial dysfunction and dysregulated lipid metabolism and to assess the efficacy of GMI in rescuing sarcopenic obesity both in vitro and in vivo.MethodsWe generated mouse strain with Dnaja3 heterozygosity (HSA‐Dnaja3f/+) specifically in skeletal muscle. The body weight, body composition, and locomotor activity of WT and HSA‐Dnaja3f/+ mice were examined. The isolated skeletal muscles and primary myoblasts from the WT and HSA‐Dnaja3f/+ mice, at young or old age, were utilized to study the molecular mechanisms, mitochondrial respiration and ROS level, mitochondrial proteomes, and serological analyses, respectively. To evaluate the therapeutic efficacy of GMI, both short‐term and long‐term GMI treatment were administrated intraperitoneally to the HSA‐Dnaja3f/+ young (4 weeks old) or adult (3 months old) mice for a duration of either 1 or 6 months, respectively.ResultsMuscular Dnaja3 heterozygosity resulted in impaired locomotor activity (P < 0.05), reduced muscular cross‐sectional area (P < 0.0001), and up‐regulation of lipogenesis (ACC2) and pro‐inflammation (STAT3) in skeletal muscles (P < 0.05). Primary myoblasts from the HSA‐Dnaja3f/+ mice displayed impaired mitochondrial respiration (P < 0.01) and imbalanced mitochondrial ROS levels. A systemic proteomic analysis of the purified mitochondria from the primary myoblasts was conducted to show the abnormalities in mitochondrial function and fatty acid metabolism (P < 0.0001). At age of 13 to 14 months, the HSA‐Dnaja3f/+ mice displayed increased body fat mass (P < 0.001), reduced fat‐free mass (P < 0.01), and impaired glucose and insulin tolerance (P < 0.01). The short‐term GMI treatment improved locomotor activity (P < 0.01) and down‐regulated the protein levels of STAT3 (P < 0.05), ACC2, and mitochondrial respiratory complex III (UQCRC2) (P < 0.01) via DNAJA3 activation. The long‐term GMI treatment ameliorated fat mass accumulation, glucose intolerance, and systemic inflammation (AST) (P < 0.05) in skeletal muscle, while enhancing thermogenesis (UCP1) (P < 0.01) in eWAT. GMI treatment promoted myogenesis, enhanced oxygen consumption, and ameliorated STAT3 (P < 0.01) through DNAJA3 activation (P < 0.05) in vitro.ConclusionsMuscular Dnaja3 haploinsufficiency dysregulates mitochondrial function and lipid metabolism then leads to sarcopenic obesity. GMI emerges as a therapeutic regimen for sarcopenic obesity treatment through DNAJA3 activation.

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DNAJA3/Tid1 Is Required for Mitochondrial DNA Maintenance and Regulates Migration and Invasion of Human Gastric Cancer Cells

Cited by 20 publications

References 80 publications

Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence

Loss of Tid1/DNAJA3 Co-Chaperone Promotes Progression and Recurrence of Hepatocellular Carcinoma after Surgical Resection: A Novel Model to Stratify Risk of Recurrence

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

Regimen on Dnaja3 haploinsufficiency mediated sarcopenic obesity with imbalanced mitochondrial homeostasis and lipid metabolism

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