Novel prognostic implications of YTH domain family 2 in resected hepatocellular carcinoma

Abstract

N6-methyladenosine (m 6 A), the most abundant internal RNA modification, serves a critical role in cancer development. However, the clinical implications of m 6 A in hepatocellular carcinoma (HCC) remain unclear. The present study sought to reveal the potential roles of m 6 A readers, which recognize m 6 A, in HCC. A total of 177 HCC and paired non-cancerous liver tissues from patients who underwent hepatectomy were analysed using quantitative PCR for the expression of m 6 A readers: YT521-B homology domain family 1 (YTHDF1) and YT521-B homology domain family 2 (YTHDF2). The expression levels of both YTHDF1 and YTHDF2 were not significantly different between tumour and non-cancerous tissues (P= 0.93 and P= 0.7, respectively). Analysis of the association between clinical features and m 6 A reader expression revealed that YTHDF1 expression was associated with formation of capsule (P= 0.02), whereas low YTHDF2 expression was associated with septal formation (P= 0.02). Furthermore, high YTHDF1 expression and high YTHDF2 expression were significantly associated with shorter recurrence-free survival (RFS) [YTHDF1: Mean survival time (MST), 34.0 vs. 19.0 months, P= 0.014; YTHDF2: MST, 30.1 vs. 12.9 months, P= 0.0032], whereas YTHDF1 and YTHDF2 expression was not significantly associated with overall survival (OS) (YTHDF1: MST, 99.4 vs. 70.2 months, P= 0.74; YTHDF2: MST, 98.4 vs. 64.1 months, P= 0.28). According to multivariate analysis, serosal invasion [hazard ratio (HR), 2.39; 95% CI 1.30-4.42; P= 0.005), portal vein or hepatic vein invasion (HR, 2.82; 95% CI 1.26-6.28; P= 0.01) and YTHDF2 expression in HCC tissues (HR, 1.85; 95% CI 1.09-3.15; P= 0.02) were identified as significant independent prognostic factors for RFS. α-fetoprotein (HR, 1.79; 95% CI 1.10-2.92; P= 0.02), serosal invasion (HR, 1.99; 95% CI 1.17-3.34; P= 0.01) and portal vein or hepatic vein invasion (HR, 3.02; 95% CI 1.38-6.61; P= 0.006) were identified as significant independent prognostic factors for OS. In conclusion, the present study revealed that high YTHDF2 expression, an m 6 A reader, in HCC tissues was associated with cancer recurrence.

Clinical implications of m6A‐related regulators YTHDF1 and YTHDF2 in hepatocellular carcinoma

“…Nakagaw et al compared YTHDF2 mRNA expression in 177 HCC and related normal liver tissues using quantitative real‐time polymerase chain reaction (qRT‐PCR), and they found no statistically major changes. However, there was a significant correlation between high YTHDF2 expression and shorter RFS (but not OS), indicating that YTHDF2 expression in HCC tissues is a pivotal, independent prognostic factor in the assessment of RFS 34 . These studies suggest that YTHDF2 expression is elevated in HCC, it is expressed in both the cytoplasm and nucleus, and that the expression was related to the poor prognosis.…”

“…However, when Nakagaw et al used qRT‐PCR to compare YTHDF1 expression in HCC and surrounding liver tissues of 177 HCC patients, they observed no statistically significant differences. High levels of YTHDF1 expression were linked to a lower RFS but showed no association with OS 34 . Moreover, Hou et al found no statistically significant difference in the expression of YTHDF1 when they utilized quantitative real‐time polymerase chain reaction (qRT‐PCR) to examine 51 matched sets of liver cancer and adjacent tissues 11 .…”

PA2G4 promotes the metastasis of hepatocellular carcinoma by stabilizing FYN mRNA in a YTHDF2-dependent manner

“…Hypoxia in HCC resulted in decreased expression of YTHDF2, and then induced aggressive transition of HCC cells by enhancing proliferation, migration, invasion abilities, together with neo-vascular formation and inflammation [ 42 , 48 ]. At the same, numerous researches revealed YTHDF2 as an oncogenic promoter in HCC, evidenced by elevated expression in HCC compared with normal liver tissues and pro-metastatic effects in animal models [ 31 , 49 ]. Specially, YTHDF2 was found to promote the liver cancer stem cell phenotype and lung metastasis by enhancing the translation of OCT4 mRNA [ 31 ], and was an independent risk factor for recurrence after hepatectomy [ 49 ].…”

“…At the same, numerous researches revealed YTHDF2 as an oncogenic promoter in HCC, evidenced by elevated expression in HCC compared with normal liver tissues and pro-metastatic effects in animal models [ 31 , 49 ]. Specially, YTHDF2 was found to promote the liver cancer stem cell phenotype and lung metastasis by enhancing the translation of OCT4 mRNA [ 31 ], and was an independent risk factor for recurrence after hepatectomy [ 49 ]. In our research, PA2G4 was found to promote EMT of liver cancer cells by stabilizing mRNA of FYN in a YTHDF2 dependent manner, and was an independent risk factor for recurrence.…”

N6-Methyladenosine RNA-Binding Protein YTHDF1 in Gastrointestinal Cancers: Function, Molecular Mechanism and Clinical Implication

“…Hence, high YTHDF1 expression is a major risk factor for predicting poor prognosis of HCC patients, including worse overall survival and progression-free survival [46,47]. Besides, high YTHDF1 expression is correlated with shorter recurrence-free survival after HCC resection [48,49]. YTHDF1 in conjunction with other m 6 A regulators, such as METTL3 and YTHDF2, could also be used to stratify high-risk HCC patients [50][51][52][53].…”