Characterization of a new murine cell line of sarcomatoid hepatocellular carcinoma and its application for biomarker/therapy development

Yen, Chia-Hung; Lai, Chih Chung; Liao, Chen Chung; Wang, Sheng-Fan; Liao, Yi Jen; Tung, Chien Yi; Hung, Jan Jong; Huang, Shiu Feng; Chen, Yi Ming Arthur

doi:10.1038/s41598-017-03164-3

Cited by 4 publications

(4 citation statements)

References 45 publications

(58 reference statements)

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“…The most widely accepted theory is the conversion theory, which postulates that the sarcomatous element derives from the carcinoma during tumor evolution[ 3 , 9 , 22 - 25 ]. Several recent studies indicate that epithelial-mesenchymal transition is an important mechanism underlying the sarcomatous change, which further confirms the conversion theory[ 26 - 28 ]. Sarcomatoid HCCs comprise variable proportions of sarcomatous and carcinomatous components.…”

Section: Discussionsupporting

confidence: 75%

Clinicopathological characteristics and surgical outcomes of sarcomatoid hepatocellular carcinoma

Wang¹,

Yao²,

Sun³

et al. 2020

WJG

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BACKGROUND Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and the fourth leading cause of cancer-related death worldwide. Sarcomatoid HCC, which contains poorly differentiated carcinomatous and sarcomatous components, is a rare histological subtype of HCC that differs from conventional HCC. It is highly aggressive and has a poor prognosis. Its clinicopathological characteristics, surgical outcomes and underlying mechanisms of its highly aggressive nature have not been fully elucidated. AIM To examine the clinicopathological characteristics and surgical outcomes of sarcomatoid HCC and explore the histogenesis of sarcomatoid HCC. METHODS In total, 196 patients [41 sarcomatoid HCC and 155 high-grade (Edmondson-Steiner grade III or IV) HCC] who underwent surgical resection between 2007 and 2017 were retrospectively reviewed. The characteristics and surgical outcomes of sarcomatoid HCC were compared with those of patients with high-grade HCC. The histological composition of invasive and metastatic sarcomatoid HCCs was evaluated. RESULTS Sarcomatoid HCC was more frequently diagnosed at an advanced stage with a larger tumor and higher rates of nonspecific symptom, adjacent organ invasion and lymph node metastasis than high-grade HCC (all P < 0.05). Compared with high-grade HCC patients, sarcomatoid HCC patients are less likely to have typical dynamic imaging features of HCC (44.4% vs 72.7%, P = 0.001) and elevated serum alpha-fetoprotein levels (> 20 ng/mL; 36.6% vs 78.7%, P < 0.001). The sarcomatoid group had a significantly shorter median recurrence-free survival (5.6 mo vs 16.4 mo, log-rank P < 0.0001) and overall survival (10.5 mo vs 48.1 mo, log-rank P < 0.0001) than the high-grade group. After controlling for confounding factors, the sarcomatoid subtype was identified as an independent predictor of poor prognosis. Pathological analyses indicated that invasive and metastatic lesions were mainly composed of carcinomatous components. CONCLUSION Sarcomatoid HCC was associated with a more advanced stage, atypical dynamic imaging, lower serum alpha-fetoprotein levels and a worse prognosis. The highly aggressive nature of sarcomatoid HCC is perhaps mediated by carcinomatous components.

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Section: Discussionsupporting

confidence: 75%

Clinicopathological characteristics and surgical outcomes of sarcomatoid hepatocellular carcinoma

Wang¹,

Yao²,

Sun³

et al. 2020

WJG

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“…However, studies on pulmonary hypertension show that the key enzyme in this pathway G6PD, plays a critical role in hypoxia-induced CD133+ progenitor cells self-renewal 39 . Similarly, in sarcomatoid hepatocellular carcinoma showed co-expression of CD133 and G6PD had poor prognosis 40 .…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

et al. 2019

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Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a "fail-safe" mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the "stress" conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-non-coding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.

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“…As expected, the expression of dnMST4 significantly increased the sphere-forming efficiency (SFE), which can be used to evaluate the population of cancer stem-like cells (CSLCs) [38], whereas the forced expression of MST4 reduced that (Figure 3E and 3F). Sarcomatoid hepatocellular carcinoma (SHC) is a rare type of HCC with positive expression of vimentin and predominantly composed of anaplastic spindle-like cells [39][40][41]. CK8 positive staining is used for differentiating SHC from real sarcomas [40].…”

Section: Mst4 Repressed the Emt Phenotype Of Hcc Cellsmentioning

confidence: 99%

“…Sarcomatoid hepatocellular carcinoma (SHC) is a rare type of HCC with positive expression of vimentin and predominantly composed of anaplastic spindle-like cells [39][40][41]. CK8 positive staining is used for differentiating SHC from real sarcomas [40]. EMT is implicated in the development of this cancer [42].…”

Section: Mst4 Repressed the Emt Phenotype Of Hcc Cellsmentioning

confidence: 99%

MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis

Dian¹,

Li²,

Li³

et al. 2021

J. Cancer

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Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods : Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo . The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro , and facilitates their intrahepatic metastasis in vivo , whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC.

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Characterization of a new murine cell line of sarcomatoid hepatocellular carcinoma and its application for biomarker/therapy development

Cited by 4 publications

References 45 publications

Clinicopathological characteristics and surgical outcomes of sarcomatoid hepatocellular carcinoma

Clinicopathological characteristics and surgical outcomes of sarcomatoid hepatocellular carcinoma

Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence

MST4 negatively regulates the EMT, invasion and metastasis of HCC cells by inactivating PI3K/AKT/Snail1 axis

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