Proliferation-inhibiting pathways in liver regeneration

Abstract

Liver regeneration, an orchestrated process, is the primary compensatory mechanism following liver injury caused by various factors. The process of liver regeneration consists of three stages: Initiation, proliferation and termination. Proliferation‑promoting factors, which stimulate the recovery of mitosis in quiescent hepatocytes, are essential in the initiation and proliferation steps of liver regeneration. Proliferation‑promoting factors act as the 'motor' of liver regeneration, whereas proliferation inhibitors arrest cell proliferation when the remnant liver reaches a suitable size. Certain proliferation inhibitors are also expressed and activated in the first two steps of liver regeneration. Anti‑proliferation factors, acting as a 'brake', control the speed of proliferation and determine the terminal point of liver regeneration. Furthermore, anti‑proliferation factors function as a 'steering‑wheel', ensuring that the regeneration process proceeds in the right direction by preventing proliferation in the wrong direction, as occurs in oncogenesis. Therefore, proliferation inhibitors to ensure safe and stable liver regeneration are as important as proliferation‑promoting factors. Cytokines, including transforming growth factor‑β and interleukin‑1, and tumor suppressor genes, including p53 and p21, are important members of the proliferation inhibitor family in liver regeneration. Certain anti‑proliferation factors are involved in the process of gene expression and protein modification. The suppression of liver regeneration led by metabolism, hormone activity and pathological performance have been reviewed previously. However, less is known regarding the proliferation inhibitors of liver regeneration and further investigations are required. Detailed information regarding the majority of known anti‑proliferation signaling pathways also remains fragmented. The present review aimed to understand the signalling pathways that inhbit proliferation in the process of liver regeneration.

Revisiting the liver: from development to regeneration - what we ought to know!

“…It has been proposed that these factors would act as a "brake", controlling the speed of proliferation and the terminal point of the process, and even ensuring the right direction, preventing oncogenesis. An extensive review focused in the termination phase has been recently published (Liu and Chen, 2017). For this reason, this phase is as important as the previous ones, and more studies should be performed to decipher its molecular mechanisms.…”

Large-Scale Profiling of Signaling Pathways Reveals a Distinct Demarcation between Normal and Extended Liver Resection

“…Then, growth factors and cytokines guide the progression of liver regeneration through expression of several cell-cycle-related proteins mainly by PI3K/AKT, wnt/β-catenin, Ras/MAPK, and JAK/STAT signaling pathways [2]. Equally important are pathways that control the speed of proliferation and determine the terminal point of liver regeneration [3]. Previously, we demonstrated that expression and activation of p21, an inhibitor of a subset of cyclin dependent kinases including cdc2, is a pivotal factor in arrested liver regeneration [4].…”

“…P21 is a fundamental cell cycle control checkpoint regulator, in particular, as it is inhibiting the G2-M phase progression. As such, it is downstream of many signaling networks, including those induced by p53, injury, growth factors (TGF-β), and inflammatory cytokines [3].…”

Tissue repair brakes: A common paradigm in the biology of regeneration

“…In liver, TGF‐β as well as other cytokines like TNF‐α, IL‐1, and IL‐6 function as inhibitors of regeneration (reviewed in Liu et al). Likewise, p53 inhibition with antisense oligonucleotides or in p53 −/− mice, leads to increased hepatocyte proliferation, although p53 function in other organs might be different .…”

“…Likewise, p53 inhibition with antisense oligonucleotides or in p53 −/− mice, leads to increased hepatocyte proliferation, although p53 function in other organs might be different . Along this line, other oncogenes such as p21, Bcl‐2, and NDRG2 have been shown to inhibit liver regeneration (reviewed in Liu et al).…”