Ascending E2F7a/b ratio facilitates KLF13 transcription in hepatocellular carcinoma and correlates with the abundance of binuclear hepatocytes (ABH) modulation for short-term recurrence

Abstract

Short-term recurrence after surgery severely threatens patients' lives and leads to dismal outcomes in hepatocellular carcinoma (HCC). Our previous research proposed the abundance of binuclear hepatocytes (ABH) as an independent indicator related to the cytokinesis regulator Anillin and significantly associated with HCC recurrence. The exact mechanism of ABH modulation has not been clearly illustrated. In this study, we intensively investigated the probable regulation mechanism and noticed a contradiction between E2F7 upregulation and ABH attenuation. As we discovered, E2F7 has two isoforms, E2F7a and E2F7b, and we innovatively define a value of the E2F7a/b ratio using a cutoff value of 6.5. E2F7 upregulation in the paracancerous tissues was predominantly presented by the E2F7a isoform, leading to an increase in the E2F7a/b ratio, instead of E2F7b as a main component in non-cancerous tissues, and is associated with short-term recurrence. We further found that KLF13 transcriptionally promotes Anillin expression in HCC and was suppressively impacted by E2F7b, but not by the highly expressed E2F7a. Hence, the ascending E2F7a/b ratio induced significant upregulation of KLF13 and participated in the attenuation of ABH in the paracancerous liver tissues. In conclusion, E2F7 presents a particular expression status in HCC by predominantly upregulating E2F7a rather than E2F7b. The ascending E2F7a/b ratio weakens the suppressive effect on KLF13 transcription and sequentially participates in ABH attenuation, associated with short-term HCC recurrence post-operation.