A Novel Mechanism of the c-Myc/NEAT1 Axis Mediating Colorectal Cancer Cell Response to Photodynamic Therapy Treatment

Abstract

Photodynamic therapy (PDT) is considered a potential treatment regimen for colorectal cancer cases (CRC). p53 signaling and the miR-124/iASPP axis play an essential role in the PDT resistance of CRC cells. PDT treatment downregulated NEAT1 expression in p53wt HCT116 and RKO cells. In these two cell lines, NEAT1 silencing enhanced the suppressive effects of PDT on cell viability and apoptosis. Within the subcutaneously implanted tumor model, NEAT1 silencing enhanced PDT-induced suppression on tumor growth. Regarding p53-deleted HCT116 cells, PDT only moderately affected cell proliferation but induced downregulation of NEAT1. NEAT1 directly targeted miR-124, acting as a ceRNA, competing with iASPP for miR-124 binding, and counteracting miR-124–mediated repression on iASPP under PDT treatment. NEAT1 silencing was enhanced, whereas miR-124 inhibition attenuated PDT effects on CRC cells; miR-124 inhibition significantly reversed the roles of NEAT1 silencing in PDT-treated CRC cells. miR-124 negatively correlated with NEAT1 and iASPP, respectively, whereas NEAT1 and iASPP positively correlated with each other. PDT downregulated c-Myc in CRC cells, and c-Myc activated the transcription of NEAT1 through the targeting of its promoter region. Within p53mut SW480 cells, PDT failed to alter cell viability and apoptosis but still downregulated c-Myc, NEAT1, and iASPP and upregulated miR-124. In p53 mutant high-abundant CRC tissues, c-Myc and NEAT1 were up-regulated, and miR-124 was downregulated. In c-Myc high-abundant CRC tissues, NEAT1 and iASPP were up-regulated, and miR-124 was downregulated. The critical role of the c-Myc/NEAT1 axis in mediating CRC response to PDT treatment via the miR-124/iASPP/p53 feedback loop was conclusively demonstrated.

Molecular Interactions of the Long Noncoding RNA NEAT1 in Cancer

“…One of the biggest obstacles to treating colorectal cancer is the lack of a molecular biomarker. Studies have shown that NEAT1 expression is upregulated in colorectal cancer tissues, and a higher level of NEAT1 contributes to the poor overall survival and disease-free survival [ 44 , 45 ]. Moreover, NEAT1 can also promote the proliferation and metastasis of colorectal cancer in vivo and in vitro [ 44 , 45 ].…”

“…Studies have shown that NEAT1 expression is upregulated in colorectal cancer tissues, and a higher level of NEAT1 contributes to the poor overall survival and disease-free survival [ 44 , 45 ]. Moreover, NEAT1 can also promote the proliferation and metastasis of colorectal cancer in vivo and in vitro [ 44 , 45 ]. NEAT1 can elevate the expression of some growth factors and transcription factors such as IGF2, GDNF, and BACH1, which facilitate the progression of colorectal cancer [ 44 , 46 , 47 ].…”

ceRNA Network of lncRNA/miRNA as Circulating Prognostic Biomarkers in Non-Hodgkin Lymphomas: Bioinformatic Analysis and Assessment of Their Prognostic Value in an NHL Cohort

“…Given the role of NEAT1 in cancer, several studies have been trying to unravel the molecular mechanisms regulating its expression and its targets. Recently, a study by Liu et al reported that NEAT1 is transcriptionally regulated by MYC, inducing its transcription [ 55 ]. Interestingly, a study by Zhu et al demonstrated that NEAT1 regulates chromatin remodeling through increasing acetylation levels at MYC promoter, inducing its expression, in colorectal cancer [ 56 ].…”

Emerging roles for lncRNA-NEAT1 in colorectal cancer

“…NEAT1 knockdown facilitated the sensitivity of CRC cells to PDT and suppressed the effect of PDT on CRC growth through sponging miR-124It has been demonstrated that the p53 deletion or mutation can induce CRC cells resistance to PDT. The c-Myc/miR-124/NEAT1/p53/iASPP axis exerted their regulatory role in CRC response to the chemotherapy [ 111 ]. It was revealed that cleavage of gasdermin E (GSDME) as a member of the gasdermin family altered apoptosis to pyroptosis as a lytic cell death which is correlated with chemotherapy along with anticancer immunity in CRC [ 112 – 115 ].…”