Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.

Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma.

The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP-TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease. 

Hippo signalling in the liver: role in development, regeneration and disease

1294 HCC is the fifth most common cancer worldwide affecting one million individuals annually. Despite advances in the detection and treatment of the disease, mortality rate remains high because current therapies are limited by the emergence of chemotherapy-resistant cancer cells. Recent research efforts in stem cell biology suggest that tumors are organized in a hierarchy of heterogeneous cell populations and that the capability to maintain tumor formation and growth specifically resides in a small population of cells called cancer stem cells (CSCs). The stem cell-like characteristics of these cells and their limited number within the bulk of the tumor are believed to account for their capability to escape conventional therapies. There is accumulating evidence showing that normal and cancer stem cells share common properties, thus we hypothesized that the identification of normal stem cells may lend insight into the understanding of the events that regulate these cells and consequences of their subversion. Liver regeneration is believed to rely on a subset of stem/progenitor cells, thus we began by studying what normal stem cells are involved in the liver regeneration process using a severe partial hepatectomy (PH) model where over 70% of the liver mass was removed. cDNA microarray analysis on RNA samples from mouse liver that was subjected to PH found Prominin-1, the mouse homologue of human CD133, to be dramatically up-regulated during the early restoration of the liver (day 3) with its expression diminishing at the final stages of liver regeneration (day 7). CD133 expression in cultured cell lines is found to correlate with the ability of the cells to develop tumor in vivo. Functional studies on isolated CD133+ and CD133- cells from human HCC cell lines and xenograft tumors found CD133+ cells to be inherently more tumorigenic than CD133- cells, showing a greater colony-forming efficiency, higher proliferative output and greater ability to form tumor in vivo. As few as 1000 CD133+ cells are sufficient for consistent tumor development in SCID mice while at least 50x as many CD133- cells are necessary to generate a tumor in the same model. Moreover, CD133+ cells are found to be endowed with characteristics similar to those of stem cells including the preferential expression of “stemness” genes; the ability to self-renew and the ability to differentiate into non-hepatocyte-like lineages. Further, CD133 is found to be maintained in very few numbers in CD133+ induced xenograft tumors and is also found to represent only a minority of the tumor cells in human HCC specimen. In addition, CD133+ cells are more resistant to doxorubicin (DOX) and fluorouracil (5-FU), anticancer drugs commonly used in treating HCC patients. The identification of tumorigenic liver CSCs in this study should not only provide new insight into the process of hepatocarcinogenesis but also open new avenues to the development of more effective cancer therapies.

Identification and characterization of tumorigenic liver cancer stem/progenitor cells

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

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Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Rare ATG7 genetic variants predispose patients to severe fatty liver disease.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

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MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Knockdown of Atg7 suppresses Tumorigenesis in a murine model of liver cancer.

Hepatocellular carcinoma (HCC) is a high incidence cancer and a major health concern worldwide. Among the many molecular signaling pathways that are dysregulated in HCC, the Ras mitogen-activated protein kinase (Ras/Raf/MAPK) signaling pathway has gained renewed attention from basic and clinical researchers. Mutations in Ras and Raf genes which are known to activate the Ras/Raf/MAPK signaling pathway have been infrequently detected in human HCC; however, the Ras/Raf/MAPK signaling pathway is activated in more than 50% of HCC cases, suggesting an alternative mechanism for the activation of the signaling pathway. Kinase suppressor of Ras acts as a molecular scaffold for facilitating the assembly of Ras/Raf/MAPK signaling pathway components and has been implicated in the regulation of this signaling pathway. In this review, we provide important insights into the cellular and molecular mechanisms involved in the activation of the Ras/Raf/MAPK signaling pathway and discuss potential therapeutic strategies for HCC. (J Liver Cancer 2021;21:1-11)

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Ras Mitogen-activated Protein Kinase Signaling and Kinase Suppressor of Ras as Therapeutic Targets for Hepatocellular Carcinoma

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. pISSN 2288-8128 eISSN 2383-5001 https://doi.org/10.17998/jlc.17.1.1 대한간암학회지 2017;17:1-14 Review

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Simon Weonsang Ro

Papers

MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Knockdown of Atg7 suppresses Tumorigenesis in a murine model of liver cancer.

Ras Mitogen-activated Protein Kinase Signaling and Kinase Suppressor of Ras as Therapeutic Targets for Hepatocellular Carcinoma

Animal Models of Liver Cancer: Current Status and Application in Preclinical Research