HLA complex P5 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly malignant tumor that threatens human health. Long noncoding RNA (lncRNA) is widely expressed in eukaryotes and is closely associated with human disease progression. However, its role in ESCC remains incompletely understood. In this study, we analyzed the results of three gene expression omnibus (GEO) databases containing lncRNA expression data of ESCC and normal tissues. The results showed that HCP5 was significantly overexpressed in ESCC tissues, which was further verified in our collected ESCC samples. The functional study suggested that HCP5 knockdown inhibited ESCC cell proliferation and invasion. Regarding the mechanism, HCP5 was able to directly interact with YTHDF1, a N6-methyladenosine (m 6 A) reader, enhancing the binding of YTHDF1 to m 6 A-modified HK2 mRNA, leading to increasing HK2 stability, thereby promoting the Warburg effect (aerobic glycolysis) of ESCC cells. The nude mice model showed that the knockdown of HCP5 in vivo remarkably reduced tumor size. Clinically, high HCP5 was positively correlated with larger tumor volume, higher TNM stage and lymph node metastasis. Moreover, ESCC patients with high HCP5 exerted shorter survival time than patients with low HCP5. These findings uncover the importance of HCP5 in human ESCC progression; the turbulence of HCP5/YTHDF1/HK2 axis may be responsible for ESCC carcinogenicity.

The Role of m6A Modification and m6A Regulators in Esophageal Cancer

“…Glucose transporter 1 (GLUT1) and hexokinase 2 (HK2) are rate-limiting enzymes of the “Warburg effect”, responsible for glucose transport and transformation, respectively. Based on multiple public databases, some studies showed a relation between the expression of these two enzymes and m 6 A regulators, which hinted that m 6 A-modified genes participated in glucose metabolic reprogramming [ 66 , 125 , 166 ], which was validated in some cytological experiments [ 69 , 71 ]. Pyruvate kinase M2 isozyme (PKM2), as a downstream gene of APC regulated by METTl3, METTL14 and YTHDF2, enhanced aerobic glycolysis and, in turn, promoted the proliferation of ESCC cells [ 69 ].…”

“…Thus, the A allele of rs5746136 in SOD2 was associated with a reduced risk of bladder cancer [ 57 ]. m 6 A could deposit on various type of RNA, such as coding RNA and non-coding RNA, participate in all steps of RNA metabolism and post-transcriptionally regulate the expression of the gene ( Table 1 ) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ].…”

“…The m 6 A regulators affected the biological behavior of ESCC cells through the same or a different gene/signaling pathway, which is shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 , Figure 6 and Figure 7 [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 124 , 126 , 127 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 141 ].…”

“…YTHDF1 could recognize, bind and increase the stability of m 6 A-modified HK2 mRNA and upregulate the expression of HK2, which mediated the role of HCP5 in promoting the progression of ESCC. In this process, METTL3 acted as a methyltransferase of HK2 mRNA [ 71 ].…”

“…FTO promoted proliferation of ESCC cells by upregulating expression of LINC00022 in a YTHDF2-dependent pattern; ( G ) Ref. [ 71 ] YTHDF1 increased stability of m 6 A-modified HK2 mRNA and upregulated expression of HK2, which mediated the role of HCP5 in promoting progression of ESCC. In this process, METTL3 acted as methyltransferase of HK2 mRNA; ( H ) Ref.…”