Heterogeneous ribonucleoprotein (hnRNP) A1 is a member of the A/B subfamily of ubiquitously expressed hnRNPs, which have a wide variety of functions in gene expression and signal transduction. To ...investigate the biological function and clinical significance of hnRNP A1 in hepatocellular carcinoma (HCC), we measured hnRNP A1 expression in four HCC cell lines and two independent cohorts of HCC patients. We found that hnRNP A1 was overexpressed in the highly metastatic HCC cell lines and in tumor tissues of patients with recurrent HCC. Knockdown of hnRNP A1 in highly metastatic HCC cells caused a significant decrease in cell invasion, while upregulation of hnRNP A1 in poorly metastatic HCC cells led to a significant increase in their invasive capacity. We found that this effect may occur through the regulation of CD44v6 expression by hnRNP A1 in HCC cells. Both quantitative reverse transcription‐polymerase chain reaction (qRT‐RCR) and immunohistochemistry revealed that hnRNP A1 was upregulated in HCC tissues and coincided with overexpression of CD44v6. HCC patients with high hnRNP A1 tended to have higher levels of CD44v6, shorter overall survival (OS) and higher rates of tumor recurrence. Multivariate analyses revealed that hnRNP A1 alone or in combination with CD44v6 were independent prognostic indicators for OS and time to recurrence and have potential as therapeutic targets. In conclusion, overexpression of hnRNP A1 promotes HCC invasion by regulating the level of CD44v6 and indicates a poor prognosis for HCC patients after curative resection.
What's new?
This study indicates that hnRNP A1 is positively related to the metastatic potential of hepatocellular carcinoma (HCC) cells and that overexpression of hnRNP A1 promotes HCC cells invasion through the regulation of CD44v6 expression. Overexpression of hnRNP A1 predicts lower overall survivor and higher recurrence rates for HCC patients after curative resection. The expression levels of hnRNP A1 alone or in combination with CD44v6 in HCC patients are important because they may provide not only a predictor for HCC prognosis but also a therapeutic target for future studies.
MiRNA-30a (miR-30a) was previously reported as one of metastatic hepatocellular carcinoma (HCC)-related microRNAs. However, the function of miR-30a on enhancing our biological understanding of HCC ...metastasis is not clear. This study demonstrated that miR-30a was significantly down-regulated in HCC tissues and cell lines, and was associated with vascular invasion, metastasis potential and recurrent disease in HCC. Functional studies confirmed that miR-30a could inhibit the metastasis of HCC in a well-established nude mouse model of lung metastasis. Moreover, miR-30a was proved to prevent anoikis inhibition of HCC cells in vivo and in vitro. Mechanically, autophagy related protein Beclin 1 and Atg5 were direct downstream targets of miR-30a, and mediated autophagy activity influence of miR-30a in HCC. Taken together, downregulated miR-30a in metastatic HCC mediates Beclin 1 and Atg5-dependent autophagy, which confers anoikis resistance in HCC cells. The molecular basis of autophagy action during this process partly contributes to the HCC metastasis, suggesting that targeting autophagy via miR-30a may have therapeutic implications for the prevention of HCC recurrence/metastasis.
•miR-30a expression is correlated with metastasis in HCC.•miR-30a inhibits the metastasis of HCC in vivo.•miR-30a prevents anoikis inhibition of HCC cells in vivo and in vitro.•Downregulated miR-30a in metastatic HCC mediates Beclin 1 and Atg5-dependent autophagy.
Macrophages are a major component of the leukocyte infiltrate of tumors and play a pivotal role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanisms by which ...macrophages promote HCC invasion are poorly understood. The present study was undertaken to investigate the relationship between macrophages and epithelial-mesenchymal transition (EMT) of HCC. Double-staining immunohistochemistry was used to observe the association between macrophages and EMT markers in clinical HCC samples and it showed that EMT primarily occurred at the edge of the tumor nest, in which infiltrating macrophages were always observed. This indicated that CD68 which is a marker of macrophages, was correlated with EMT marker levels. In addition, after being cultured with macrophages for 24 h, the ability of HCC cells to migrate and invade increased, Snail and N-Cadherin expression was upregulated, and E-Cadherin was downregulated. An antibody array assay was applied to analyze the supernatant of these cultures and it demonstrated IL-8 increased significantly in the macrophage co-culture system. Finally, the role of macrophage-derived IL-8 in the invasion of HCC cells was assayed, and downstream signaling pathways were also investigated. We found that IL-8: i) may induce EMT and promote HCC cell migration and invasion and ii) is associated with the JAK2/STAT3/Snail signaling pathway. Taking together, these findings revealed that macrophages that have infiltrated tumors may induce epithelial-mesenchymal transition of HCC cells via the IL-8 activated JAK2/STAT3/Snail pathway. Thus, this may offer a potential target for developing new HCC therapies.
Oxaliplatin-based chemotherapy is widely used to treat hepatocellular carcinoma (HCC). Recent studies suggested that therapeutic resistance of tumors was affected by tumor microenvironment (TME). As ...a major component of TME, the role of tumor-associated macrophages (TAMs) on drug resistance in HCC is largely unknown.
26 HCC samples were obtained from patients who had underwent transarterial chemoembolization (TACE) within 3 months before receiving curative resections. Immunohistochemistry was applied to detect the density of TAMs in these tissues. SMMC-7721 and Huh-7 cell lines were used to co-culture with THP-1 derived macrophages. Under oxaliplatin treatment, cell death was measured using MTT and annexin V/propidium iodide assays. Autophagy activation was evaluated by GFP-LC3 redistribution and LC3 conversion in SMMC-7721 and Huh-7. Short-interfering RNA against ATG5 gene was applied to inhibit autophagy. In vivo validation was conducted in Huh-7 with or without macrophages using an HCC xenograft model in nude mice after oxaliplatin administration.
We found that the density of TAMs in HCC samples was associated with the efficacy of TACE. Macrophages inhibited cell death induced by oxaliplatin in HCC cells. Autophagy was functionally activated in HCC cells after co-culturing with macrophages. Suppression of autophagy using RNA interference of ATG5 in HCC cells promoted the oxaliplatin cytotoxicity in the co-culture system. Critically, co-implantation with macrophages in HCC xenografts weakens cytotoxic effect of oxaliplatin through inducing autophagy to avoid apoptosis.
Our results suggest that TAMs induce autophagy in HCC cells which might contribute to oxaliplatin resistance. Targeting TAMs is a promising therapeutic strategy to enhance the effects of chemotherapy oxaliplatin in HCC patients.
Hepatocellular carcinoma (HCC) has a complex and changeable tumor microenvironment. Despite emerging evidence focusing on autophagy process within immune cells, the function and regulatory mechanism ...of macrophage autophagy in tumor progression remains unclear. Our results of multiplex-immunohistochemistry and RNA-sequencing identified the reduced levels of autophagy in tumor macrophages in the HCC microenvironment, associated with a poor prognosis and increased microvascular metastasis in HCC patients. Specifically, HCC suppressed the macrophage autophagy initiation through the up-regulation of mTOR and ULK1 phosphorylation at Ser757. Knockdown of autophagy-related proteins to further inhibit autophagy significantly boosted the metastatic potential of HCC. Mechanistically, the accumulation of NLRP3 inflammasome mediated by autophagy inhibition promoted the cleavage, maturation, and release of IL-1β, which facilitated the HCC progression, eventually accelerating HCC metastasis via the epithelial-mesenchymal transition. Autophagy inhibition provoked macrophage self-recruitment through the CCL20-CCR6 signaling was also a crucial account of HCC progression. Recruited macrophages mediated the cascade amplification of IL-1β and CCL20 to form a novel pro-metastatic positive feedback loop through promoting HCC metastasis and increased macrophage recruitment, respectively. Notably, targeting IL-1β/IL-1 receptor signaling impaired lung metastasis induced by macrophage autophagy inhibition in a mice HCC lung metastasis model. In summary, this study highlighted that inhibition of tumor macrophage autophagy facilitated HCC progression by increasing IL-1β secretion via NLRP3 inflammasome accumulation and by macrophage self-recruitment through the CCL20 signaling pathway. Interruption of this metastasis-promoting loop by IL-1β blockade may provide a promising therapeutic strategy for HCC patients.
Background
The concurrent presence of liver cirrhosis and hepatocellular carcinoma (HCC) poses a challenge for laparoscopic surgeons to establish a routine practice. The aim of this study was to ...gather evidence and produce recommendations on the safe and effective practice of laparoscopic hepatectomy for patients with solitary HCC (≤ 5 cm) and liver cirrhosis.
Methods
Between October 2013 and October 2014, 356 curative hepatectomies were performed for patients pathologically diagnosed with solitary HCC (≤ 5 cm) accompanied by cirrhosis (stage 4 fibrosis). To overcome selection bias, a 1:2 match using propensity score matching analysis was conducted between laparoscopic and open hepatectomy. Perioperative outcomes were compared between the groups, including hospitalization, operation time, blood loss, and surgical complications. Perioperative inflammation-based markers, including systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were collected from medical records and analyzed.
Results
There were 43 and 77 patients in the laparoscopic and open groups, respectively. The laparoscopic group had less hepatic inflow occlusion (16.3% vs. 61%;
P
< 0.001), shorter operation time (155 vs. 170 min;
P
= 0.004), and shorter postoperative hospital stay (4 vs. 7 days;
P
< 0.001). Although the difference was not significant (
P
= 0.154), the rate of postoperative complications tended to be lower in the laparoscopic group (2.3%) compared with the open group (9.1%). The increase in postoperative SII, NLR, and LMR for laparoscopic hepatectomy were significantly lower than for open hepatectomy. NLR < 5.8 on postoperative day 3 was significantly correlated with shorter hospital stay (
P
< 0.001).
Conclusions
Compared with open hepatectomy, laparoscopic hepatectomy for selected HCC patients, even in the presence of cirrhosis, might result in better perioperative outcomes and postoperative inflammatory response attenuation, and ultimately promote faster recovery. This provides evidence for considering routine laparoscopic hepatectomy through careful selection of patients with HCC.
The sole and integrated effects of N rates and cropping patterns on grain yield advantage (a-c), and carbon emission efficiency advantage (d-f). Notes: CEE, the carbon emission efficiency; N1-150, ...N2-225, and N3-300 represented three N levels of 150, 225 and 300 kg ha−1, respectively.
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•Soybean intercropped with wheat or maize promoted LER, showing plant facilitation.•Plant facilitation increased LER and reduced nitrogen application by increasing NUE.•Facilitation promoted carbon emission (CE) with C&N degradation enzyme activity.•Wheat-maize intercropping showed opposite trend due to interspecific competition.•Plant facilitation increased carbon emission efficiency (yield/CE) but lowered N application.
It is critical to reduce carbon (C) emission and nitrogen (N) input in agroecosystems under a changing climate. If crop diversification is introduced, interspecific plant–plant interactions as an effective pathway may achieve this goal. However, the related process and its mechanism are poorly understood. A two-year field study was conducted to explore the effects of intercropping systems including soybean-maize, soybean- wheat and maize-wheat on the land equivalent ratio (LER), nitrogen use efficiency (NUE), seasonal carbon emission, and soil properties in a typical semiarid environment. Three N rates (N1: 150 kg ha−1, N2: 225 kg ha−1, N3: 300 kg ha−1) were applied. The result indicated that the intercropping with soybean significantly increased system productivity with LER > 1, showing a typical plant–plant facilitation. However, the LER of maize–wheat intercropping was significantly lower than 1, representing interspecific competition. With the increasing N rate, the productivity of monoculture wheat or maize was evidently promoted. Particularly, the productivity under N2 and N3 remained at a similar level due to interspecific facilitation. This trend was mechanically driven by the improved N uptake (NLER > 1) and NUE under the presence of interspecific facilitation. Critically, interspecific facilitation was observed to promote carbon emissions (CE) by 4.0%-6.3%, since root input, microbial activities and the C&N decomposition enzyme activities were significantly enhanced. To say, interspecific facilitation evidently enhanced carbon emission efficiency (Yield/CE) whereas interspecific competition turned to lower it. To sum up, plant facilitation improved crop productivity and carbon emission efficiency by reducing N input. Our findings provided a new insight into the exploration of green solution in terms of reducing emissions and increasing efficiency, as well as lowering N fertilizer application in the natural and agricultural ecosystems.
•Hepatocellular carcinoma cells domesticated macrophages toward M2-phenotype polarization.•Human HCC tumor microarrays and in vivo tumor models showed autophagy inhibition of macrophages.•The ...autophagy inhibition of macrophages participated in M2-like macrophage polarization.•The inhibition increased the instability of the NF-κB pathway via ubiquitination degradation of TAB3.
The tumor microenvironment is a highly heterogeneous circumstance composed of multiple components, while tumor-associated macrophages (TAMs) are major innate immune cells with highly plastic and are always educated by tumor cells to structure an advantageous pro-tumor immune microenvironment. Despite emerging evidence focalizing the role of autophagy in other immune cells, the regulatory mechanism of autophagy in macrophage polarization remains poorly understood. Herein, we demonstrated that hepatocellular carcinoma (HCC) cells educated macrophages toward M2-like phenotype polarization under the condition of coculture. Moreover, we observed that inhibition of macrophage autophagy promoted M2-like macrophage polarization, while the tendency was impeded when autophagy was motivated. Mechanistically, macrophage autophagy inhibition inactivates the NF-κB pathway by increasing the instability of TAB3 via ubiquitination degradation, which leads to the M2-like phenotype polarization of macrophages. Both immunohistochemistry staining using human HCC tissues and experiment in vivo verified autophagy inhibition is correlated with M2 macrophage polarization. Altogether, we illustrated that macrophage autophagy was involved in the process of HCC cells domesticating M2 macrophage polarization via the NF-κB pathway. These results provide a new target to interfere with the polarization of macrophages to M2-like phenotype during HCC progression.
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•A novel functionalized ionic liquid was synthesized for the Mo(VI)/U(VI) separation in HNO3.•The highest SF of Mo(VI) over U(VI) exceeds 104, thus setting a new record for their ...separation.•Even after five cycles, BHIBNTf2 can still extract more than 97 % of Mo(VI).•This work achieves efficient separation of Mo(VI) from U(VI) and is expected to optimize existing processes.
We describe here a hydroxyoxime-functionalized ionic liquid, 1-butyl-3-(4-hydroxy-3-((hydroxyimino)methyl)benzyl)-1H-imidazol-3-ium bis((trifluoromethyl)sulfonyl)amide (BHIBNTf2), for the isolation and purification of 99Mo from 235U. This material exhibits remarkable extraction efficiency for Mo(VI) from 0.1 to 2 M HNO3 and can effectively distinguish Mo(VI) from U(VI). The attained highest separation factor (SF) of Mo(VI) over U(VI) exceeds 104, thus setting a new record for their separation. Additionally, the extracted Mo(VI) can be efficiently recovered using either NH4OH or the mixture of NH4OH and (NH4)2CO3. This excellent extraction performance is sustained even after five cycles. The extraction efficiency remains stable following exposure to 150 kGy gamma irradiation, thus providing robust experimental support for potential engineering applications. Slope analysis and EXAFS results indicate that BHIBNTf2 forms a 2:1 complex with Mo(VI) during the extraction process primarily driven by a cation exchange mechanism. When one equivalent of Mo(VI) migrates from the aqueous phase to the organic phase, each of two equivalents BHIBNTf2 remove one of H+ and migrate to the aqueous phase to maintain charge balance. This investigation introduces a highly efficient and environmentally benign method for separation, alongside providing novel insights into ligand design for the efficacious differentiation of Mo(VI) and U(VI) under HNO3 conditions, potentially streamlining current methodologies.
Abstract
Background
Combination conversion therapies afforded curative surgery chance for initially unresectable hepatocellular carcinoma (uHCC). This study aimed to evaluate the conversion rate and ...clinical outcomes of a first-line conversion regimen of lenvatinib combined with transarterial chemoembolization (TACE) plus immunotherapy for initial uHCC by interpreting real-world data.
Methods
Conversion therapy data of patients with uHCC from November 2018 to January 2021 were analysed. The regimens included triple combination therapy (t-CT: lenvatinib, TACE, plus toripalimab) and dual combination therapy (d-CT: lenvatinib plus TACE). Another study population diagnosed with hepatocellular carcinoma of macrovascular invasion disease were included as the upfront surgery cohort. Treatment responses and conversion rate were primary outcomes. Survival and adverse events were analysed.
Results
Fifty-one patients receiving t-CT (n = 30) and d-CT (n = 21) were enrolled. Higher overall response rates (76.7 per cent versus 47.6 per cent, P = 0.042) and disease control rates (90.0 per cent versus 57.1 per cent, P = 0.042) were observed via t-CT than d-CT. Both median overall survival and event-free survival were not reached in the t-CT cohort. A higher rate of curative conversion resection was achieved through t-CT than d-CT (50.0 per cent versus 19.0 per cent, P = 0.039). The disease-free survival of patients undergoing conversion resection in the t-CT cohort (n = 15) was higher than that in the upfront surgery cohort (n = 68, P = 0.039). Both t-CT and d-CT regimens were tolerable.
Conclusions
Better treatment responses and conversion rate for patients with uHCC were obtained with first-line t-CT. Neoadjuvant t-CT before surgery should be recommended for patients with macrovascular invasion.
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