Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma

Liu, Chang; Ren, Yifan; Dong, Jian; Ke, Mengyun; Ma, Feng; Monga, Satdarshan P.; Wu, Rongqian; Lv, Yi; Zhang, Xufeng

doi:10.1016/j.canlet.2017.09.013

Cited by 30 publications

(32 citation statements)

References 52 publications

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“…In tumor cells, overexpression of cyclin D1 and down-regulation or dysfunction of its negative regulatory proteins P21 and P27 are very common, these changes are closely related to the abnormal proliferation of tumors. Molecular mechanisms leading to this abnormal expression include overexpression of oncogenes such as c-Myc [29], FBXO22 [30], miR-95-3p [31], deletion or mutation of tumor suppressor gene such as P53 [32], and abnormal activation of the cancer-promoting signaling pathways such as PI3K/AKT pathway [32][33][34]. In the present study, we noted an abnormal overexpression of cyclin D1 in Hep3B cells both at the mRNA and protein levels.…”

Section: Discussionsupporting

confidence: 57%

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

et al. 2020

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The overall survival rate of patients with hepatocellular carcinoma (HCC) has remained unchanged over the last several decades. Therefore, novel drugs and therapies are required for HCC treatment. Isoliquiritigenin (ISL), a natural flavonoid predominantly isolated from the traditional Chinese medicine Glycyrrhizae Radix (Licorice), has a high anticancer potential and broad application value in various cancers. Here, we aimed to investigate the anticancer role of ISL in the HCC cell line Hep3B. Functional analysis revealed that ISL inhibited the proliferation of Hep3B cells by causing G1/S cell cycle arrest in vitro. Meanwhile, the inhibitory effect of ISL on proliferation was also observed in vivo. Further analysis revealed that ISL could suppress the migration and metastasis of Hep3B cells in vitro and in vivo. Mechanistic analysis revealed that ISL inhibited cyclin D1 and up-regulated the proteins P21, P27 that negatively regulate the cell cycle. Furthermore, ISL induced apoptosis while inhibiting cell cycle transition. In addition, phosphatidylinositol 3′-kinase/protein kinase B (PI3K/AKT) signal pathway was suppressed by ISL treatment, and the epithelial marker E-cadherin was up-regulated when the mesenchymal markers Vimentin and N-cadherin were down-regulated. In brief, our findings suggest that ISL could be a promising agent for preventing HCC tumorigenesis and metastasis.

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Section: Discussionsupporting

confidence: 57%

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

et al. 2020

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“…The overexpression of Notch1 in HCC cells leads to enhanced cell proliferation . In this study, we found that CD147 overexpression promoted the Notch1 classical downstream target Sox9 , which has been proven to be a liver progenitor cell marker and to promote HCC cell proliferation . Thus, CD147 promotes HCC proliferation via the Notch1‐Sox9 signaling pathway.…”

Section: Discussionmentioning

confidence: 58%

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

Yong

Zhang

Liu

et al. 2019

The Journal of Pathology

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The γ‐secretase complex is a presenilin‐dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ‐secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ‐secretase complex inhibitor and CD147‐directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ‐secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Previous studies have revealed that genetic alterations of chromosomes X and Y are frequently observed in patients with HCC, including chromosome-specific gene change, oncogene and/or tumor suppressor gene expression and structural rearrangements of chromosomes (9,11,77). This indicates that genes located on sex chromosomes may be responsible for HCC (78,79).…”

Section: Sex Chromosomes Are Involved In Sex Disparity In Hccmentioning

confidence: 99%

“…SRY has been recognized as an oncogene and cancer stem cell promoter in male HCC in in vitro studies (85,86). Liu et al (9) reported overexpression of SRY in ~84% of male patients with HCC. A liver-specific transgenic murine model with overexpression of SRY was susceptible to DEN-induced hepatocarcinogenesis compared with age-and sex-matched wild-type mice (9).…”

Section: Sex-determining Region On the Y Chromosome (Sry)mentioning

confidence: 99%

“…The sex disparity of HCC has demonstrated that the ratio of estrogen and testosterone levels may be associated with the initiation and progression of HCC, suggesting that active estrogen-and androgen-mediated signaling pathways may regulate the risk of HCC (7,8). In recent years, increasing attention has been focused on the genetic alterations of sex chromosomes, which may be responsible for the sex disparity in HCC (9)(10)(11). Considerable efforts have been exerted in exploring the molecular mechanisms involved in the sex disparity in HCC (7-9).…”

Section: Introductionmentioning

confidence: 99%

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Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma (Review)

Jia

et al. 2019

Oncol Lett

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Hepatocellular carcinoma (HCC) is more frequently observed and aggressive in men compared with women. Increasing evidence demonstrates that the sex disparity appears to be mediated by the stimulatory effects of androgens and the protective effects of estrogen in the development and progression of HCC. In the past few decades, studies on the sex difference of HCC mainly focused on the effect of sex hormones on the transactivation of hepatitis B virus X protein and the release of inflammatory cytokines, and these studies have further intensified in recent years. Sex hormones are also involved in genetic alterations and DNA damage repair in hepatocytes through binding to their specific cellular receptors and affecting the corresponding signaling pathways. Furthermore, the theory of sex chromosomes participating in HCC has been considered. The present review discussed the recent advances in the molecular mechanisms of sex disparity in HCC, with the aim of improving the understanding of the underlying critical factors and exploring more effective methods for the prevention and treatment of HCC. Contents

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Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma

Cited by 30 publications

References 52 publications

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

Gamma‐secretase complex‐dependent intramembrane proteolysis of CD147 regulates the Notch1 signaling pathway in hepatocellular carcinoma

Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma (Review)

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