Downregulation of TFAM inhibits the tumorigenesis of non-small cell lung cancer by activating ROS-mediated JNK/p38MAPK signaling and reducing cellular bioenergetics

Xie, Deyao; Wu, Xiaoyi; Lan, Linhua; Shangguan, Fugeng; Liu, Xiaoming; Chen, Fuhong; Xu, Shan; Zhang, Ya; Chen, Zilei; Huang, Kate; Wang, Rongrong; Wang, Lu; Song, Xiaoxiao; Liu, Yongzhang; Lü, Bin

doi:10.18632/oncotarget.7018

Cited by 67 publications

(72 citation statements)

References 37 publications

(36 reference statements)

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“…It was reported that TFAM depletion could result in upregulation of the levels of proapoptotic Bax, p21, tumor suppressor p53, and p-p53 (ser15), as well as poly ADP ribose polymerase (PARP), caspase 3 and caspase 9 cleavage [16]. In our study, TFAM knockdown by miR-214 mimic could reduce NF-κB nuclear translocation in vivo and in vitro.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 52%

“…Previous report demonstrated that down-regulation of TFAM in non-small cell lung cancer could activate reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase(JNK)/ p38 mitogen-activated protein kinase (MAPK) signaling and reduce cellular bioenergetics which resulted in cell cycle arrest [16]. It was found in this study that TFAM expression could lead to the enhanced NF-κB activity as well as the promoted NF-κB dependent gene expression.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 63%

“…In addition, the TFAM mRNA and protein levels were reported to be significantly elevated in a poorly differentiated rat hepatoma (Morris hepatoma) [39]. Increased TFAM expression levels were also observed in non-small cell lung cancer (NSCLC) and positively correlated to the malignancy and tumor grade as well [16].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

“…TFAM is reported to be associated with tumorigenesis in breast, cervical, prostate, small cell lung cancers [12][13][14][15][16]. Also, frequent frameshift mutations in the coding mononucleotide repeat of TFAM was demonstrated in sporadic CRC derived cell lines and CRC tissues [17,18].…”

Section: Introductionmentioning

confidence: 99%

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Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

Zhan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Colon cancer, also known as colorectal cancer (CRC), is one of the most common malignant tumors globally. Although significant advances have been made for developing novel therapeutics, the mechanisms of progression of colorectal cancer are still poorly understood. Methods: In this study, we identified down-regulation of microRNA-214 (miR-214) as the contributing factor for CRC. Mitochondrial transcription factor A (TFAM) and miR-214 expression in tumor samples from colorectal cancer patients and cancer cell lines were examined by reverse transcription and real-Time PCR (qPCR) or Western Blotting. Results: Our data demonstrated that miR-214 was significantly down-regulated in the tissue samples from CRC patients as well as CRC derived cell lines. TFAM overexpression was also observed in CRC patients and identified as a target for miR-214. Knockdown of TFAM by miR-214 mimics significantly inhibited the proliferation of CRC cell lines. Also, down-regulation of TFAM inhibited nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear translocation and the expression of NF-κB depended genes. Conclusion: In conclusion, our data suggested that down-regulation of MiR-214 contributed to the enhanced TFAM expression and decreased proliferation of CRC cells.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 52%

Section: Cellular Physiology and Biochemistrymentioning

confidence: 63%

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

Zhan

et al. 2018

Cell Physiol Biochem

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“…A previous study also revealed that antioxidants may effectively restrain ROS generation and apoptosis caused by UVA (28). The generated ROS activates the upstream activating agent and apoptosis signal conditioning kinase 1 (AsKI) of p38 and c-Jun N-terminal kinase, so as to activate p38, indicating that ROS-ASKI-p38MAPK pathway is an important signal transduction pathway in the carcinogenic effects of ultraviolet light (29). In the present study it was revealed that salvianolic acid B increased ROS generation levels and the silencing of p38 expression inhibited the anticancer effect of salvianolic acid B on the level of ROS generation in the MG63 cell line.…”

Section: Discussionmentioning

confidence: 96%

Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

et al. 2017

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Abstract. The present study aimed to investigate the potential anticancer effect and mechanisms of salvianolic acid B on osteosarcoma. Salvianolic acid B suppressed osteosarcoma cell proliferation and induced apoptosis in the osteosarcoma MG63 cell line, and activated the expressions of cleaved caspase-3, phosphorylated-tumor protein (p)38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated-p53 (p-p53) proteins in the MG63 cells. Additionally, Salvianolic acid B also increased the level of reactive oxygen species (ROS) generation in the MG63 cells. The silencing of p38 expression inhibited the anticancer effect of salvianolic acid B on the levels of cell proliferation, p-p53 protein expression and ROS generation level in the MG63 cells. All these data supported the hypothesis that the anticancer effect of salvianolic acid B includes the suppression of cell proliferation and induces apoptosis in MG63 cells, and that p38 is important in the anticancer effect of salvianolic acid B on osteosarcoma cells due to the direct regulation of ROS generation. These data suggest that salvianolic acid B is important in the proliferation of osteosarcoma cells due to the direct regulation of p38-mediated ROS signaling. IntroductionOsteosarcoma is a type of primary malignant tumor that exhibits the highest morbidity of all neoplasms in the human skeletal system, and often presents in the metaphysis of the long tubal bones (1). Osteosarcoma often affects young people between the age of 20 and 30 years old. The mortality rate is high (2) and ~20% of patients exhibit pulmonary metastasis prior to diagnosis. Subsequent to diagnosis, the majority of patients succumb to the disease within 2 years (2). At present, there are no effective therapeutic treatments for early osteosarcoma (3). Therefore, it is important to investigate the causes of osteosarcoma occurrence, development and invasion, the mechanisms of osteosarcoma oncogenesis, and to identify effective diagnostic and therapeutic techniques. The development of gene therapy has created novel research targets in oncotherapy, including the identification of a target gene (4).Mitogen-activated protein kinase (MAPK) is the one of the most important types of signal conduction pathway in humans, and interacts with multiple signaling pathways (5). The tumor protein (p)38 MAPK pathway is activated through phosphotyrosine and threonine and inflammatory and growth factors, and activates downstream transcription factors on target genes, increases the initiation of cancer cell development, promotes protein synthesis, regulates cell surface receptors and regulates the invasion and transfer of tumor cells (6).Reactive oxygen species (ROS) are secondary products in the process of aerobic metabolism and include oxygen ions, peroxide and oxygen radical molecules (7). The increase in the level of intracellular ROS may promote cellular proliferation and differentiation to some extent. However, excessive levels of ROS results in damage to lipids, proteins and DNA, destroying numerous nor...

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Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer

Yang

Zhao

et al. 2021

Cancer Communications

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Background Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC). Methods TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM△IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. Results The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. Conclusions TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.

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Downregulation of TFAM inhibits the tumorigenesis of non-small cell lung cancer by activating ROS-mediated JNK/p38MAPK signaling and reducing cellular bioenergetics

Cited by 67 publications

References 37 publications

Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

Down-Regulation of MicroRNA-214 Contributed to the Enhanced Mitochondrial Transcription Factor A and Inhibited Proliferation of Colorectal Cancer Cells

Salvianolic acid B suppresses cell proliferation and induces apoptosis in osteosarcoma through p38-mediated reactive oxygen species generation

Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer

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