Upregulation of the c-MYC oncogene and adjacent long noncoding RNAs PVT1 and CCAT1 in esophageal squamous cell carcinoma

Abstract

Background All cell types express long non-coding RNAs (lncRNAs), which have the potential to play a role in carcinogenesis by altering the levels of their expression. Squamous cell carcinoma of the esophagus (ESCC) is a deadly disease with a poor prognosis and a high frequency of lymphatic metastases. Understanding the functional role and signaling pathways of two neighboring lncRNAs, CCAT1 and PVT1, in this oncogene’s pathogenesis may help us determine ESCC. Furthermore, it is still unclear whether these lncRNAs are linked to the clinicopathological characteristics of patients with ESCC. Methods For this study, we used biopsy from the Imam Khomeini Cancer Institute’s tumor bank in Tehran, Iran to obtain 40 ESCC tumor samples and their normal margin counterparts. The expression levels of the CCAT1, PVT1, and c-MYC genes were assessed using quantitative Real-Time RT-PCR. Additionally, demographic data and clinical-pathologic characteristics, such as tumor grade, tumor stage, lymph node, and metastasis, were taken into consideration. Graphpad prism version 8 was used for bioinformatics analyses. Results Comparing ESCC tissues to non-tumor tissues, we found significant upregulation of PVT1, CCAT1, and c-MYC. Patients with ESCC who had increased PVT1 expression also had higher rates of advanced stage and lymph node metastasis, whereas increased CCAT1 expression was only linked to advanced stage and wasn’t associated with lymph node metastasis. In predicting ESCC, CCAT1 (p < 0.05) was found to be an important factor. Overall survival was reduced by c-MYC and PVT1 overexpression (p < 0.001), according to Kaplan-Meier analysis. PVT1, CCAT1, and c-MYC were found to interact with 23 miRNAs with high and medium score classes, as shown in a bioinformatics study. We summarized the experimentally proven interactions between c-MYC, PVT1, and CCAT1 and other miRNAs, lncRNAs, and proteins. Conclusion This is the first report that CCAT1, PVT1 and c-MYC have been found to be up-regulated simultaneously in ESCC. It is possible that these genes may be involved in ESCC as a result of these findings. Therefore, as consequence, more research is needed to determine whether or not these lncRNAs play an oncogenic role in ESCC development and progression, as well as the regulatory mechanisms that control them.

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers

“…Research on non-coding, regulatory RNAs, such as miRNA or lncRNA, is one of the emerging fields of research in recent decades. Regulatory RNAs are molecules that coordinate post-transcriptionally in a very fine-grained and usually complex network during many cellular processes [ 35 ]. Several miRNAs and lncRNAs have been associated with the regulation of MYC in various tumors.…”

“…Several miRNAs and lncRNAs have been associated with the regulation of MYC in various tumors. Several of them act directly on the MYC 3′ UTR and promoter regions, repressing the function of MYC, as in miR24 [ 36 ], Let-7 [ 37 , 38 ] and miR-138 [ 39 ], or promoting it, as in CCAT1 and PVT1 [ 31 , 35 ], while others play an indirect role in the functional regulation of MYC in both directions ( Figure 1 B). For example, MNX1-AS1 promotes MYC/E2F1 stability via IGF2BP1, forming a positive feedback loop [ 40 ].…”

“…The two most prominent and most researched lncRNAs, CCAT1 (alias CASC19) and PVT1 are located on opposite sides, in close vicinity to MYC . The upregulation of both lncRNAs was characteristic for several tumor types, including breast, gastric, ovarian, lung, esophageal, liver or colon cancers [ 31 , 35 , 110 ]. It was also shown that MYC amplification alone failed to increase protein levels, but co-amplification with PVT1 may stabilize the MYC protein by protecting it from phosphorylation and subsequent degradation, suggesting that co-amplification is an obligatory event in MYC-driven tumors [ 31 , 35 , 111 ].…”

“…The upregulation of both lncRNAs was characteristic for several tumor types, including breast, gastric, ovarian, lung, esophageal, liver or colon cancers [ 31 , 35 , 110 ]. It was also shown that MYC amplification alone failed to increase protein levels, but co-amplification with PVT1 may stabilize the MYC protein by protecting it from phosphorylation and subsequent degradation, suggesting that co-amplification is an obligatory event in MYC-driven tumors [ 31 , 35 , 111 ]. In vitro studies in CRC also showed that PVT1 has multiple spliced transcripts with distinct preferences for nuclear and cytoplasmic regions, assuming different roles in regulatory processes.…”