Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the ...increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat‐treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat‐treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness‐dependent regulation of ERK phosphorylation. Heat‐exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness‐dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat‐treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.
Increased matrix stiffness after thermal ablation accelerates the progression of heat‐exposed residual HCC cells. Vitamin K1 and sorafenib disrupt the stiffness‐induced ERK activation to reverse the pro‐tumor effect as the potential therapeutic drugs. This new finding will help design strategy to treat the local tumor progression and prevent its rapid progression after RFA in the treatment of medium or large HCC.
Transarterial chemoembolization (TACE) is the standard treatment for unresectable hepatocellular carcinoma (HCC). Hypoxia‐induced angiogenesis by TACE is linked to treatment failure; however, whether ...the chemotherapeutic damage of TACE to HCC could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy‐damaged HCC cells on the neo‐angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (GDF15) was significantly upregulated in HCC cells exposed to chemotherapeutic agents. GDF15 from chemotherapy‐damaged HCC cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro‐angiogenic effect of GDF15 was through the activation of Src and its downstream AKT, MAPK, and NF‐κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy‐damaged HCC cells‐promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in TACE to HCC could promote tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro‐angiogenic effects.
Chemotherapeutic damage to hepatocellular carcinoma promotes tumor angiogenesis via the increased release of GDF15. Thalidomide could reverse these pro‐angiogenic effects.
Some evidences show that residual tumor after thermal ablation will progress rapidly. However, its mechanisms remain unclear. Here, we assessed whether activated HSCs could regulate stem cell-like ...property of residual tumor after incomplete thermal ablation to promote tumor progression. Human HCC cell lines were exposed to sublethal heat treatment to simulate the peripheral zone of thermal ablation. After residual HCC cells were cultured with conditional medium (CM) from activated HSCs, parameters of the stem cell-like phenotypes were analyzed. Nude mice bearing heat-exposed residual HCC cells and HSCs were subjected to metformin treatment to thwarter tumor progression. CM from activated primary HSCs or LX-2 cells significantly induced the stem cell-like phenotypes of residual HCC cells after heat treatment. These effects were significantly abrogated by neutralizing periostin (POSTN) in the CM. POSTN regulated the stemness of heat-exposed residual HCC cells via activation of integrin β1/AKT/GSK-3β/β-catenin/TCF4/Nanog signaling pathway. Metformin significantly inhibited in vivo progression of heat-exposed residual HCC via suppressing POSTN secretion and decreasing cancer stem cell marker expression. Our data propose a new mechanism of activated HSCs promoting the stemness traits of residual HCC cells after incomplete thermal ablation and suggest metformin as a potential drug to reverse this process.
Tumor cell invasion into the surrounding matrix has been well documented as an early event of metastasis occurrence. However, the dynamic expression patterns of proteins during early invasion of ...hepatocellular carcinoma (HCC) are largely unknown. Using a three-dimensional HCC invasion culture model established previously, we investigated the dynamic expression patterns of identified proteins during early invasion of HCC.
Highly metastatic MHCC97H cells and a liver tissue fragment were long-term co-cultured in a rotating wall vessel (RWV) bioreactor to simulate different pathological states of HCC invasion. The established spherical co-cultures were collected on days 0, 5, 10, and 15 for dynamic expression pattern analysis. Significantly different proteins among spheroids at different time points were screened and identified using quantitative proteomics of iTRAQ labeling coupled with LC-MS/MS. Dynamic expression patterns of differential proteins were further categorized by K-means clustering. The expression modes of several differentially expressed proteins were confirmed by Western blot and qRT-PCR.
Time course analysis of invasion/metastasis gene expressions (MMP2, MMP7, MMP9, CD44, SPP1, CXCR4, CXCL12, and CDH1) showed remarkable, dynamic alterations during the invasion process of HCC. A total of 1,028 proteins were identified in spherical co-cultures collected at different time points by quantitative proteomics. Among these proteins, 529 common differential proteins related to HCC invasion were clustered into 25 types of expression patterns. Some proteins displayed significant dynamic alterations during the early invasion process of HCC, such as upregulation at the early invasion stage and downregulation at the late invasion stage (e.g., MAPRE1, PHB2, cathepsin D, etc.) or continuous upregulation during the entire invasion process (e.g., vitronectin, Met, clusterin, ICAM1, GSN, etc.).
Dynamic expression patterns of candidate proteins during the early invasion process of HCC facilitate the discovery of new molecular targets for early intervention to prevent HCC invasion and metastasis.
Abstract
Transarterial chemoembolization (
TACE
) is the standard treatment for unresectable hepatocellular carcinoma (
HCC
). Hypoxia‐induced angiogenesis by
TACE
is linked to treatment failure; ...however, whether the chemotherapeutic damage of
TACE
to
HCC
could increase tumor angiogenesis has not been explored. The molecular effects of chemotherapy‐damaged
HCC
cells on the neo‐angiogenesis were investigated in vitro and in vivo. The expression of growth differentiation factor 15 (
GDF
15) was significantly upregulated in
HCC
cells exposed to chemotherapeutic agents.
GDF
15 from chemotherapy‐damaged
HCC
cells promoted the in vitro proliferation, migration, and tube formation of endothelial cells. The pro‐angiogenic effect of
GDF
15 was through the activation of Src and its downstream
AKT
,
MAPK
, and
NF
‐κB signaling, which was blocked by thalidomide. The use of thalidomide significantly attenuated the in vivo chemotherapy‐damaged
HCC
cells‐promoted angiogenesis in nude mice. In conclusion, the chemotherapeutic damage in
TACE
to
HCC
could promote tumor angiogenesis via the increased release of
GDF
15. Thalidomide could reverse these pro‐angiogenic effects.
Human cytomegalovirus (HCMV) is an opportunistic prototypic beta-herpesvirus that can cause severe and even fatal diseases in immune-naive newborns and immunocompromised adults. Host-virus ...interactions occurring at the transcriptional and posttranscriptional levels are critical for establishing an HCMV latent or lytic infection, but the mechanisms remain poorly understood. Herein, we investigated the expression of circRNAs in human leukemia monocytes (THP-1 cells) latently infected with HCMV and explored the diagnostic value of circRNAs in children with HCMV infection. A total of 2,110 and 1,912 circRNAs were identified in mock-infected and HCMV latent-infected THP-1 cells, respectively. Of these, we identified 1,421 differently expressed circRNAs, of which 650 were upregulated and 771 were downregulated. The host genes corresponding to the differentially expressed circRNAs were mainly involved in the regulation of host cell secretion pathways, cell cycle, and cell apoptosis. The differentially expressed circRNAs had binding sites for microRNAs, suggesting an important role in the mechanism of HCMV latent infection. Furthermore, a clinical analysis showed that the expression levels of hsa_circ_0001445 and hsa_circ_0001206 were statistically significantly different in HCMV-infected patients vs. normal controls, suggesting that these circRNAs could potentially serve as biomarkers of HCMV-infection.
Microbial translocation (MT) and altered gut microbiota have been described in acute leukemic patients and contribute to immune activation and inflammation. However, phage translocation has not been ...investigated in leukemia patients yet. We recruited 44 leukemic patients and 52 healthy adults and quantified the levels of 3 phages in peripheral blood, which were the most positive phages screened from fecal samples. The content of 16S rRNA in plasma was detected by qPCR to assess the intestinal mucosa of these patients. Spearman’s rank correlation was used to analyze the relationship between phage load and the relevant clinical data. We found the most prevalent phages in fecal samples were λ phage, Wphi phage, and P22 phage, and λ phage had the highest detection rate in plasma (68%). Phage content was affected by chemotherapy and course of disease and correlated with the levels of CRP (
r
= 0.43,
p
= 0.003), sCD14 (
r
= 0.37,
p
= 0.014), and sCD163 (
r
= 0.44,
p
= 0.003). Our data indicate that plasma phage load is a promising marker for gut barrier damage and that gut phage translocation correlates with monocyte/macrophage activation and systemic inflammatory response in leukemic patients.
The impact of Cr6+ on the growth of lactuca sativa in Greenhouse Cucumber was investigated. The seeds of lacuna sativa Italian bolting resistance lettuce were treated by different Cr6+ concentration ...to study the effects on its seed germination and seedling growth. The results showed that the seed germination rate, vigor index of seedlings decreased with increment of Cr6+ concentration to varying degrees, and vigor germination, vigor index, raw weight, root length significantly lower. The absorption of lettuce seedlings on different nutrient elements is impacted by the concentration of Cr6+.
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