Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications

Park, See‐Hyoung; Jang, Kyu Yun; Kim, Min Jae; Yoon, Sarah; Jo, Yuna; Kwon, So Mee; Kim, Kyoung Min; Kwon, Keun Sang; Kim, Chan Young; Woo, Hyun Goo

doi:10.18632/oncotarget.6264

Cited by 42 publications

(45 citation statements)

References 41 publications

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“…Resent research report that as transcription factor, Foxo3a inhibited proliferation and induced cell cycle arrest by controlling cyclin-dependent kinase inhibitor p27kip1 [39], contributing to cancer cell apoptosis by regulation of proapoptotic member [40]. Previous reports have showed Foxo3a were overexpressed in less aggressive types of GC [41,42]. Foxo3a aberrantly downregulation in chemo-resistant gastric cancer cells was related to chemoresistance [30], which were verified in our research (Supplementary Figure S4A).…”

Section: Discussionsupporting

confidence: 88%

Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Pang

Zhou

et al. 2019

RNA Biology

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2019) Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain, RNA Biology, 16:2, 233-248, ABSTRACTThe development of chemotherapeutic drugs resistance such as doxorubicin (DOX) and cisplatin (DDP) is the major barrier in gastric cancer therapy. Emerging evidences reveal that microRNAs (miRNAs) contribute to chemosensitivity. In this study, we investigated the role of miR-633, an oncogenic miRNA, in gastric cancer chemoresistance. In gastric cancer tissue and cell lines, miR-633 expression was highly increased and correlated with down regulation of Fas-associated protein with death domain (FADD). Inhibition of miR-633 significantly increased FADD protein level and enhanced DOX/DDP induced apoptosis in vitro. MiR-633 antagomir administration remarkably decreased tumor growth in combination with DOX in vivo, suggesting that miR-633 targets FADD to block gastric cancer cell death. We found that the promoter region of miR-633 contained putative binding sites for forkhead box O 3 (Foxo3a), which can directly repress miR-633 transcription. In addition, we observed that DOX-induced nuclear accumulation of Foxo3a leaded to the suppression of miR-633 transcription. Together, our study revealed that miR-633/FADD axis played a significant role in the chemoresistance and Foxo3a regulated this pathway in gastric cancer. Thus, miR-633 antagomir resensitized gastric cancer cells to chemotherapy drug and had potentially therapeutic implication. ARTICLE HISTORY

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Section: Discussionsupporting

confidence: 88%

Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Pang

Zhou

et al. 2019

RNA Biology

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“…Finally, both enzymatic activity and transcriptional regulatory functions of PARP-1 were reported to be elevated as a function of prostate cancer progression, independently of DNA double strand breaks, but through enhancement of E2F1-mediated induction of DNA repair factors involved in HR [63]. Elevated PARP-1 mRNA and protein are associated with poor prognosis in gastric cancer [64,65]; PARP-1 mRNA is elevated in colon carcinoma when compared to adenoma [66]; PARP-1 gene expression is associated with lymph node spread of malignant pleural mesothelioma [67]; and PARP-1 mRNA and protein are elevated in endometrial adenocarcinoma [68]. Both PARP-1 mRNA and protein are highly expressed in small cell lung cancer [69], but PARP-1 protein has been shown to associate with longer progression free survival (PFS) in limited-stage small cell lung cancer [70].…”

Section: High Activity Of Parp-1 In Tumor Development and Progressionmentioning

confidence: 99%

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Pazzaglia

Pioli

2019

Cells

145

135

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PARP-1 (poly(ADP-ribose)-polymerase 1), mainly known for its protective role in DNA repair, also regulates inflammatory processes. Notably, defects in DNA repair and chronic inflammation may both predispose to cancer development. On the other hand, inhibition of DNA repair and inflammatory responses can be beneficial in cancer therapy and PARP inhibitors are currently used for their lethal effects on tumor cells. Furthermore, excess of PARP-1 activity has been associated with many tumors and inflammation-related clinical conditions, including asthma, sepsis, arthritis, atherosclerosis, and neurodegenerative diseases, to name a few. Activation and inhibition of PARP represent, therefore, a double-edged sword that can be exploited for therapeutic purposes. In our review, we will discuss recent findings highlighting the composite multifaceted role of PARP-1 in cancer and inflammation-related diseases.

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“…FOXO3 is a critical protein involved in cell cycle arrest and apoptosis (16,17). Therefore, FOXO3 is recognized as a tumor suppressor, and decreased FOXO3 expression is associated with progression of various tumors, including GC (18)(19)(20). Guo et al (21) revealed that miR-122-5p downregulated FOXO3 expression by binding to the 3'UTR of its mRNA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of apoptosis by miR‑122‑5p in α‑fetoprotein‑producing gastric cancer

et al. 2019

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α-Fetoprotein (AFP)-producing gastric cancer (AFPGC) is recognized as one of the most aggressive tumors with subsequent poor prognosis compared with common gastric cancer (GC) subtypes. However, the molecular mechanism remains to be elucidated. We previously identified that miR-122-5p could be a useful biomarker in AFPGC patients. We examined herein the biological function of miR-122-5p and the molecular mechanism underlying tumor progression in AFPGC. We used the AFPGC cell line (FU97) and miR-122-5p inhibitor to examine the function of miR-122-5p. Moreover, we investigated the possible targets of miR-122-5p. The expression level of miR-122-5p was significantly increased in the FU97 cell line than in common GC cell lines. Also, suppression of miR-122-5p significantly reduced AFP levels and proliferation in AFPGC through an induction of apoptosis. Western blotting revealed that the expression of anti-apoptotic protein (Bcl-2) was decreased and that of pro-apoptotic protein (caspase-3) was increased in miR-122-5p suppression of FU97. Moreover, we revealed that FOXO3 was an important target of miR-122-5p in AFPGC, which inhibited apoptosis and subsequently manifested aggressiveness. In conclusion, miR-122-5p inhibited apoptosis and facilitated tumor progression by targeting FOXO3 in AFPGC, which indicates the possibility of miR-122-5p as a potential therapeutic target in AFPGC.

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Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications

Cited by 42 publications

References 41 publications

Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Foxo3a-dependent miR-633 regulates chemotherapeutic sensitivity in gastric cancer by targeting Fas-associated death domain

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

Inhibition of apoptosis by miR‑122‑5p in α‑fetoprotein‑producing gastric cancer

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