Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Ohkoshi, Shogo; Yano, Masahiko; Matsuda, Yasunobu

doi:10.3748/wjg.v21.i42.12150

Cited by 32 publications

(23 citation statements)

References 77 publications

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“…In the present study, no effect on cell cycle was observed following c-Myc inhibition, which suggests that synergistic action with another signaling pathway may be required for its role on cell proliferation. c-Myc is an oncogene and p21 is a tumor suppressor gene (28). In the present study, c-Myc was demonstrated to promote RMS development by repressing p21 transcription.…”

Section: Discussionsupporting

confidence: 54%

c-Myc promotes tumor proliferation and anti-apoptosis by repressing p21 in rhabdomyosarcomas

Zhang

Song

Zang

et al. 2017

Molecular Medicine Reports

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v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) is an important member protein of the Myc family that is important in cell cycle progression, apoptosis and tumorigenesis. In the present study, the role of c‑Myc in rhabdomyosarcoma (RMS) was assessed. Firstly, expression of endogenous c‑Myc and cyclin dependent kinase inhibitor 1A (p21) was examined in normal skeletal muscle, RMS specimens and TE671 RMS cells by immunohistochemistry, reverse transcription‑quantitative polymerase chain reaction and western blotting. Furthermore, cell cycle progression and apoptosis were assessed in TE671 RMS cells following treatment with a c‑Myc inhibitor, 10058‑F4. The results demonstrated that c‑Myc was overexpressed in clinical RMS tissues and TE671 cells, with the highest expression observed in the most RMS samples. Expression of p21 protein and apoptosis function were increased following treatment with 10058‑F4, but no difference was observed in cell cycle progression. In conclusion, the present study indicated that c‑Myc promotes RMS development by inhibiting apoptosis through repression of p21 transcription. Further studies will be required to evaluate c‑Myc as a target for RMS clinical treatment.

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Section: Discussionsupporting

confidence: 54%

c-Myc promotes tumor proliferation and anti-apoptosis by repressing p21 in rhabdomyosarcomas

Zhang

Song

Zang

et al. 2017

Molecular Medicine Reports

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“…As miRNAs mainly function through directly suppressing the translation of their target genes (27), the potential target genes of miR-93 in osteosarcoma were then examined. Among the putative target genes of miR-93, P21 is a key regulator of cell cycle progression at the G1 checkpoint (28). In addition, P21 can also interact with proliferating cell nuclear antigen, a DNA polymerase accessory factor, and has a regulatory role in S phase DNA replication and DNA damage repair (29).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells

2017

Experimental and Therapeutic Medicine

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Abstract. MicroRNAs (miRNAs) are small, non-coding RNAs that are key regulators of gene expression by directly binding to the 3'-untranslated region of their target mRNAs, resulting in translational repression or degradation of mRNA. It has been demonstrated that miRNAs have key roles in a variety of human malignancies, including osteosarcoma. The present study aimed to assess the molecular mechanism of miR-93 in the regulation of osteosarcoma cell proliferation. Reverse-transcription quantitative PCR and western blot assays were used to examine mRNA and protein expression. An MTT assay and flow cytometry were performed to determine the cell proliferation and cell cycle distribution. A luciferase reporter assay was performed to confirm the direct targeting of cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as P21, by miR-93, which was suggested by a bioinformatics analysis. The results showed that the expression of miR-93 was frequently and significantly increased in a total of 19 osteosarcoma tissues compared to their matched adjacent non-tumor tissues, and the upregulation of miR-93 was associated with the malignant progression of osteosarcoma. Furthermore, miR-93 was also upregulated in the human osteosarcoma cell lines Saos-2, U2OS, SW1353 and MG63 when compared with that in the human osteoblast cell line hFOB1.19. Transfection with miR-93 inhibitor significantly reduced the miR-93 levels and inhibited the proliferation of U2OS and MG63 osteosarcoma cells. The protein levels of P21 were negatively regulated by miR-93 in U2OS and MG63 cells. Knockdown of miR-93 caused cell cycle arrest at G1 stage in U2OS and MG63 cells, identical to the effect of P21 overexpression. Finally, P21 was found to be significantly downregulated in osteosarcoma tissues compared to their matched adjacent non-tumor tissues, suggesting that the inhibition of P21 may be due to increased miR-93 expression in osteosarcoma tissues. In conclusion, the present study demonstrated that miR-93 enhances the proliferation of osteosarcoma cells, at least in part via inhibiting P21 expression and thus promoting cell cycle progression.

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“…In this experiment, stress and drug treatment increased its expression (and despite it being an HSP90 client). The cell cycle inhibitors p21/CDNK1A/CIP1/WAF1 and p27/CDKN1B/KIP1 also have pro- and anti-apoptotic functions depending on subcellular localization and mutation status [62–64]; here, their expression increases with stress and drug applications.…”

Section: Resultsmentioning

confidence: 99%

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

Graner

Hellwinkel

Lencioni

et al. 2016

International Journal of Hyperthermia

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Background Agents targeting HSP90 and GRP94 are seldom tested in stressed contexts such as heat shock (HS) or the unfolded protein response (UPR). Tumor stress often activates HSPs and the UPR as pro-survival mechanisms. This begs the question of stress effects on chemotherapeutic efficacy, particularly with drugs targeting chaperones such as HSP90 or GRP94. We tested the utility of several HSP90 inhibitors, including PU-H71 (targeting GRP94), on a primary canine lung cancer line under HS/UPR stress compared to control conditions. Methods We cultured canine bronchoalveolar adenocarcinoma cells that showed high endogenous HSP90 and GRP94 expression; these levels substantially increased upon HS or UPR induction. We treated cells with HSP90 inhibitors 17-DMAG, 17-AAG, or PU-H71 under standard conditions, HS, or UPR. Cell viability/survival were assayed. Antibody arrays measured intracellular signalling and apoptosis profiles. Results HS and UPR had varying effects on cells treated with different HSP90 inhibitors; in particular, HS and UPR promoted resistance to inhibitors in short-term assays, but combinations of UPR stress and PU-H571 showed potent cytotoxic activity in longer-term assays. Array data indicated altered signalling pathways, with apoptotic and pro-survival implications. UPR induction+dual targeting of HSP90 and GRP94 swayed the balance toward apoptosis. Conclusion Cellular stresses, endemic to tumors, or interventionally inducible, can deflect or enhance chemo-efficacy, particularly with chaperone-targeting drugs. Stress is likely not held accountable when testing new pharmacologics or assessing currently-used drugs. A better understanding of stress impacts on drug activities should be critical in improving therapeutic targeting and in discerning mechanisms of drug resistance.

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Oncogenic role of p21 in hepatocarcinogenesis suggests a new treatment strategy

Cited by 32 publications

References 77 publications

c-Myc promotes tumor proliferation and anti-apoptosis by repressing p21 in rhabdomyosarcomas

c-Myc promotes tumor proliferation and anti-apoptosis by repressing p21 in rhabdomyosarcomas

MicroRNA-93 promotes cell proliferation by directly targeting P21 in osteosarcoma cells

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

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