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Page 2 of 15 Chen et al. Hepatoma Res 2018;4:29 I http://dx.doi.org/10.20517/2394-5079.2018.18

Risks factors: Inflammation cytokines and Hepatocarcinogenic pathways:
HBV and HCV infection, chemokines: PI3K/AKT/mTOR, WNT/b-catenin,
alcohol consumption, TNF-a, IL-6, IL-1b, IL-10, COX-2, MAPK, NF-kB, VEGF, JAK/STAT,
non-alcohotic steatohepatitis VEGF, HIF-1a, MMPS, Erk, EGFR, toll receptor pathway, etc.
(NASH), Aflatoxins or Bacterias, Akt, TGF-a/b1, JNK, ERK, P38, Genetic/epigenetic/immunity
type 2 diabetes or obesity, ELK-1, AP-1, TCF, CD95, IL-1b, TERT, TP53, CTNNB1, ARID1A,
Toxic drugs or chemical, etc. IkB, TRAF-1/2, NF-kB, etc. PD1/PD-L1, etc.

Chronic injury/ Genetic/epigenetic
inflammation/ immune dysfunction
Immune response
Normal liver Fibrosis/cirrhosis liver Liver cancer

Figure 1. The multistep process of the development of liver cancer. The risk factors, inflammation cytokines and chemokines, and
hepatocarcinogenic pathways are related to the inflammation-cancer transformation during the development of primary liver cancer

intrahepatic cholangiocarcinoma (iCCA), and other rare types such as hepatoblastoma and fibrolamellar
carcinoma according to the pathological type. Tumor morphology can be divided into nodular, massive
and diffuse types of liver cancer . It's worth noting that more than 500,000 people receive a diagnosis of
[1]
HCC every year and the incidence is still increasing worldwide, by about 4% per year in men and 3% per
year in women . The number of fatal cases accounts for about 5.4% of all malignancies each year globally. It
[2]
is estimated that there will be over 1 million new cancer diagnoses of HCC each year by 2025 . China has
[3]
more than 55% liver cancer cases globally. HCC accounts for approximately 90% of primary liver cancer .
[4]
Currently, it is very limited for HCC patients to choose the suitable treatment. Over the past 2 decades, the
median survival time for advanced HCC patients is less than 1 year, and the 5-year relative survival rate
is below 9% . Patients with well-preserved liver function will select surgical resection. The most effective
[4]
way for HCC patients to improve the survival is liver transplantation. Unfortunately, those treatments
often result in a poor prognosis, including a high risk of postoperative complications and recurrence of the
tumor. Although there are various strategies, such as liver transplantation, surgical resection, target drugs
(sorafenib, lenvatinib or regorafenib) and immunotherapy (nivolumab), to extend survival time of liver
cancer patients, those treatments are not effective . It has been well recognized that HCC is a complex and
[5]
heterogeneous malignancy, caused by a variety of risks factors, including chronic inflammation by virus,
like hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol consumption, non-alcoholic steatohepatitis
(NASH), bacteria, type 2 diabetes, smoking or chemical. Age and gender are also risk factors for HCC .
[6]
HCC is more common in middle-aged men with a male to female ratio of up to (3-8):1. In China, the major
component of the attributable risk is chronic hepatitis B . Based on those different causes, the molecular
[7]
pathogenesis of HCC is very complicated. This review is intended to facilitate the understanding of the
risk factors, inflammation cytokines and hepatocarcinogenic pathways related to the inflammation-cancer
transformation during the development of primary liver cancer [Figure 1].

INFLAMMATION AND LIVER CANCER
Virchow postulated the connection between cancer and inflammation in 1863 . It has been estimated that
[8]
inflammation and chronic infection would lead to the development of about 15% human cancers . A large
[9]
number of epidemiological investigations suggest that inflammation is one of the main factors leading to
tumorigenesis or promoting tumor development . Recently, more and more data have notarized inflammation
[10]
as a critical component of HCC progression. Direct evidences suggesting chronic inflammation, especially
hepatitis B and hepatitis C, are the risk factor for HCC. Patients who have those diseases will get more risk to