Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance

Mottaghi-Dastjerdi, Negar; Soltany-Rezaee-Rad, Mohammad; Sepehrizadeh, Zargham; Roshandel, Gholamreza; Ebrahimifard, Farzaneh; Setayesh, Neda

doi:10.1186/2008-2231-22-14

Cited by 28 publications

(33 citation statements)

References 30 publications

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“…In the context of cancer, the role of HN is poorly understood. HN is overexpressed in biopsies from patients with gastric 23 and bladder cancer 24 when compared to non-neoplastic surrounding tissue. We have previously shown that HN is overexpressed in rat pituitary tumor cells, when compared to normal pituitary cells 18 .…”

Section: Discussionmentioning

confidence: 99%

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Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Ayala

Gottardo

Zuccato

et al. 2020

Sci Rep

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Humanin (HN) is a mitochondrial-derived peptide with cytoprotective effect in many tissues. Administration of Hn analogs has been proposed as therapeutic approach for degenerative diseases. Although HN has been shown to protect normal tissues from chemotherapy, its role in tumor pathogenesis is poorly understood. Here, we evaluated the effect of HN on the progression of experimental triple negative breast cancer (tnBc). the meta-analysis of transcriptomic data from the cancer Genome Atlas indicated that Hn and its receptors are expressed in breast cancer specimens. By immunohistochemistry we observed up-regulation of Hn in tnBc biopsies when compared to mammary gland sections from healthy donors. Addition of exogenous Hn protected tnBc cells from apoptotic stimuli whereas shRnA-mediated Hn silencing reduced their viability and enhanced their chemo-sensitivity. Systemic administration of HN in TNBC-bearing mice reduced tumor apoptotic rate, impaired the antitumor and anti-metastatic effect of chemotherapy and stimulated tumor progression, accelerating tumor growth and development of spontaneous lung metastases. These findings suggest that HN may exert pro-tumoral effects and thus, caution should be taken when using exogenous HN to treat degenerative diseases. In addition, our study suggests that HN blockade could constitute a therapeutic strategy to improve the efficacy of chemotherapy in breast cancer. Breast cancer is the most common cause of death by cancer in women 1. Although new strategies have been developed for the treatment of breast tumors that express hormone receptors and/or human epidermal growth factor receptor 2 (Her2), there are no therapeutic options for patients with triple negative breast cancer (TNBC), for whom chemotherapy/radiotherapy remains the first-line treatment 2,3. Since these tumors frequently develop chemo-resistance 4 , novel therapeutic targets are urgently needed to improve the treatment of TNBC. A cytoprotective mitochondrial-derived peptide, humanin (HN), was discovered in healthy neurons of patients suffering Alzheimer's disease 5. HN was the first small open reading frame (ORF) identified within the mitochondrial DNA, encoded within the 16S rRNA gene (MT-RNR2) 6. HN can be translated both in the mitochondrial matrix or the cytosol, resulting in biologically functional 21 and 24-amino acid peptides, respectively 7. Small ORFs for six other small HN-like peptides (SHLPs) have been detected in the mitochondrial genome, two of which (SHLP2 and SHLP3) exhibit biological activity 8. Thirteen MT-RNR2-like loci that encode for fifteen HN-like peptides were detected in the nuclear genome 9. However, the expression of the mitochondrial gene MT-RNR2 is substantially higher than any nuclear isoform 9. HN regulates the mitochondrial apoptotic pathway by interaction with proteins of the Bcl-2 family 10. Intracellular HN binds to proapoptotic proteins, such as Bax, tBid and BimEL inhibiting the release of cytochrome

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Section: Discussionmentioning

confidence: 99%

“…Although HN has been proposed to be a potential oncopeptide almost 2 decades ago 22 , its role in cancer development and treatment remains poorly understood. Since HN overexpression was detected in gastric cancer 23 , bladder tumor cells 24 , and pituitary tumor cells 13,18 , it was suggested that HN upregulation could play a role in tumorigenesis.…”

mentioning

confidence: 99%

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Ayala

Gottardo

Zuccato

et al. 2020

Sci Rep

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“…189 Moreover, evidence has shown that humanin contributes to chemoresistance and cancer aggressiveness. 192,193…”

Section: Mitochondrion-derived Molecules Are Involved In Mitochondriamentioning

confidence: 99%

Role of the mitochondrial stress response in human cancer progression

Wang

Chen

Tseng

et al. 2020

Exp Biol Med (Maywood)

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Mitochondria are important organelles that are responsible for cellular energy metabolism, cellular redox/calcium homeostasis, and cell death regulation in mammalian cells. Mitochondrial dysfunction is involved in various diseases, such as neurodegenerative diseases, cardiovascular diseases, immune disorders, and cancer. Defective mitochondria and metabolism remodeling are common characteristics in cancer cells. Several factors, such as mitochondrial DNA copy number changes, mitochondrial DNA mutations, mitochondrial enzyme defects, and mitochondrial dynamic changes, may contribute to mitochondrial dysfunction in cancer cells. Some lines of evidence have shown that mitochondrial dysfunction may promote cancer progression. Here, several mitochondrial stress responses, including the mitochondrial unfolded protein response and the integrated stress response, and several mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and others) are reviewed; these pathways and molecules are considered to act as retrograde signaling regulators in the development and progression of cancer. Targeting these components of the mitochondrial stress response may be an important strategy for cancer treatment. Impact statement Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.

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“…Su expresión fue detectada en cáncer gástrico, por lo que fue propuesto que la sobreexpresión de este péptido podría constituir un evento molecular impor-tante de la tumorigénesis y la quimiorresistencia del tumor (54). Más recientemente, también se informó su sobreexpresión en células tumorales de vejiga, por lo que se sugirió a la HN circulante en sangre como un potencial biomarcador para el diagnóstico de este tipo de cáncer (55).…”

Section: Hn Y Cáncerunclassified

Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

Asad¹,

Zuccato²,

Nicola-Candia³

et al. 2019

nova

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La humanina es un péptido derivado de la mitocondria con efectos protectores robustos contra una gran variedad de estímulos citotóxicos en diversos tipos celulares. Esto la convierte en un blanco terapéutico interesante para muchas enfermedades, como el cáncer y enfermedades neurodegenerativas, entre otras. Además, este péptido podría utilizarse como un biomarcador en estas enfermedades. Durante la última década, han sido desarrollados análogos y péptido-miméticos de la humanina que muestran resultados prometedores en modelos preclínicos. A su vez, también se está explorando el potencial terapéutico de vectores de terapia génica que puedan sobreexpresar o silenciar la humanina endógena.Varios puntos importantes a considerar antes de trasladar estas estrategias terapéuticas a la clínica son su posible papel en la progresión del cáncer y la eventual generación de quimiorresistencia. Todos estos temas serán abordados en este artículo de revisión.

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Genome expression analysis by suppression subtractive hybridization identified overexpression of Humanin, a target gene in gastric cancer chemoresistance

Cited by 28 publications

References 30 publications

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer

Role of the mitochondrial stress response in human cancer progression

Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

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