Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Site-Recognition-Induced Structural and Photoluminescent Evolution of the Gold-Pincer Nanocluster.

The induced structural transformation provides an efficient way to precisely modulate the fine structures and the corresponding performance of gold nanoclusters, thus constituting one of the important research topics in cluster chemistry. However, the driving forces and mechanisms of these processes are still ambiguous in many cases, limiting further applications. In this work, based on the unique coordination mode of the pincer ligand-stabilized gold nanocluster Au8(PNP)4, we revealed the site-recognition mechanism for induced transformations of gold nanoclusters. The "open nitrogen sites" on the surface of the nanocluster interact with different inducers including organic compounds and metals and trigger the conversion of Au8(PNP)4 to Au13 and Au9Ag4 nanoclusters, respectively. Control experiments verified the site-recognition mechanism, and the femtosecond and nanosecond transient absorption spectroscopy revealed the electronic and photoluminescent evolution accompanied by the structural transformation.

High-Throughput Growth of Armored Perovskite Single Crystal Fibers for Pixelated Arrays.

The poor machinability of halide perovskite crystals severely hampered their practical applications. Here a high-throughput growth method is reported for armored perovskite single-crystal fibers (SCFs). The mold-embedded melt growth (MEG) method provides each SCF with a capillary quartz shell, thus guaranteeing their integrality when cutting and polishing. Hundreds of perovskite SCFs, exemplified by CsPbBr3, CsPbCl3, and CsPbBr2.5I0.5, with customized dimensions (inner diameters of 150-1000 µm and length of several centimeters), are grown in one batch, with all the SCFs bearing homogeneity in shape, orientation, and optical/electronic properties. Versatile assembly protocols are proposed to directly integrate the SCFs into arrays. The assembled array detectors demonstrated low-level dark currents (< 1 nA) with negligible drift, low detection limit (< 44.84 nGy s-1), and high sensitivity (61147 µC Gy-1 cm-2). Moreover, the SCFs as isolated pixels are free of signal crosstalk while showing uniform X-ray photocurrents, which is in favor of high spatial resolution X-ray imaging. As both MEG and the assembly of SCFs involve none sophisticated processes limiting the scalable fabrication, the strategy is considered to meet the preconditions of high-throughput productions.

Silencing of OGDHL promotes liver cancer metastasis by enhancing hypoxia inducible factor 1 α protein stability.

Hepatocellular carcinoma (HCC) is one of the most common malignant diseases associated with a high rate of mortality. Frequent intrahepatic spread, extrahepatic metastasis, and tumor invasiveness are the main factors responsible for the poor prognosis of patients with HCC. Hypoxia-inducible factor 1 (HIF-1) has been verified to play a critical role in the metastasis of HCC. HIFs are also known to be modulated by small molecular metabolites, thus highlighting the need to understand the complexity of their cellular regulation in tumor metastasis. In this study, lower expression levels of oxoglutarate dehydrogenase-like (OGDHL) were strongly correlated with aggressive clinicopathologic characteristics, such as metastasis and invasion in three independent cohorts featuring a total of 281 postoperative HCC patients. The aberrant expression of OGDHL reduced cell invasiveness and migration in vitro and HCC metastasis in vivo, whereas the silencing of OGDHL promoted these processes in HCC cells. The pro-metastatic role of OGDHL downregulation is most likely attributed to its upregulation of HIF-1α transactivation activity and the protein stabilization by promoting the accumulation of L-2-HG to prevent the activity of HIF-1α prolyl hydroxylases, which subsequently causes an epithelial-mesenchymal transition process in HCC cells. These results demonstrate that OGDHL is a dominant factor that modulates the metastasis of HCC.

AKR1C3 suppresses ferroptosis in hepatocellular carcinoma through regulation of YAP/SLC7A11 signaling pathway.

AKR1C3 is frequently overexpressed and it is a validated therapeutic target in various tumors including hepatocellular carcinoma (HCC). Our previous study showed that AKR1C3 facilitated HCC proliferation and metastasis by forming a positive feedback loop of AKR1C3-NF-κB-STAT3. Ferroptosis is a form of iron-dependent cell death driven by iron-dependent accumulation of lipid reactive oxygen species and plays an important role in tumor suppression. However, little is known about the role of AKR1C3 in ferroptosis susceptibility. In this study, we found that knockdown of AKR1C3 potently enhanced the sensitivity of HCC cells to ferroptosis inducers both in vitro and in vivo. Overexpression of AKR1C3 protected against ferroptosis in HCC cells. Mechanistically, AKR1C3 regulated ferroptosis through YAP/SLC7A11 signaling in HCC. AKR1C3 knockdown led to a decrease in YAP nuclear translocation, resulted in the inhibition of cystine transporter SLC7A11, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. Moreover, we found that the combination of AKR1C3 and SLC7A11 was a strong predictor of poor prognosis in HCC. Collectively, these findings identify a novel role of AKR1C3 in ferroptosis, and highlighting a candidate therapeutic target to potentially improve the effect of ferroptosis-based antitumor therapy.

Effect of plan complexity on the dosimetry, delivery accuracy, and interplay effect in lung VMAT SBRT with 6 MV FFF beam.

PURPOSE: The purpose of this study is to investigate the effect of plan complexity on the dosimetry, delivery accuracy, and interplay effect in lung stereotactic body radiation therapy (SBRT) using volumetric modulated arc therapy (VMAT) with 6 MV flattening-filter-free (FFF) beam. METHODS: Twenty patients with early stage non-small cell lung cancer were included. For each patient, high-complexity (HC) and low-complexity (LC) three-partial-arc VMAT plans were optimized by adjusting the normal tissue objectives and the maximum monitoring units (MUs) for a Varian TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, CA, USA) using 6 MV FFF beam. The effect of plan complexity was comprehensively evaluated in three aspects: (1) The dosimetric parameters, including CI, D2cm, R50, and dose-volume parameters of organs at risk were compared. (2) The delivery accuracy was assessed by pretreatment quality assurance for two groups of plans. (3) The motion-induced dose deviation was evaluated based on point dose measurements near the tumor center by using a programmable phantom. The standard deviation (SD) and maximum dose difference of five measurements were used to quantify the interplay effect. RESULTS: The dosimetry of HC and LC plans were similar except the CI (1.003 ± 0.032 and 1.026 ± 0.043, p = 0.030) and Dmax to the spinal cord (10.6 ± 3.2 and 9.9 ± 3.0, p = 0.012). The gamma passing rates were significantly higher in LC plans for all arcs (p < 0.001). The SDs of HC and LC plans ranged from 0.5-16.6% and 0.03-2.9%, respectively, under the conditions of one-field, two-field, and three-field delivery for each plan with 0.5, 1, 2, and 3 cm motion amplitudes. The maximum dose differences of HC and LC plans were 34.5% and 9.1%, respectively. CONCLUSION: For lung VMAT SBRT, LC plans have a higher delivery accuracy and a lower motion-induced dose deviation with similar dosimetry compared with HC plans.

Diversity of soil fungi in the vineyards of Changli region in China.

This study aimed to elucidate the fungal diversity of Changli vineyard soil in China. High-throughput sequencing technology was used to investigate the diversity and composition of soil fungi in five vineyards from different geographical locations in Changli. Although the five vineyards had similar fungal communities, the diversity, composition, and distribution of the high-abundance species differed. Ascomycota, Basidiomycota, and Mortierellomycota were dominant phyla. Among the 14 high-abundance genera of fungi, Odiodendron, Pleotrichocladium, and Plectosephalella have rarely been reported in other vineyards and are unique to the Changli region. In addition, Solicoccozyma aeria and Solicoccozyma terrea were the dominant species in the five vineyards and have rarely been reported in domestic vineyards. Additionally, Rhizophagus, Wardomyces, Mortierella, Volutella, and Cryptococcus were significantly different among the five vineyard soils. Among these species, Mortierella was highly abundant in each vineyard, but its contents were significantly different across vineyards. These findings enrich the information on the composition and diversity of soil fungi in the vineyard of the Changli region, which helps to explore the regional or distinctive sensorial attributes of wine from the perspective of microbial biogeography.

A self-immolated fluorogenic agent triggered by H2S exhibiting potential anti-glioblastoma activity.

Glioblastoma is the most common and aggressive type of malignant brain tumor with poor survival and limited therapeutic options. Theranostic anticancer agents with dual functions of diagnosis and therapy are highly attractive. Self-immolation reaction is a promising approach for theranostic prodrugs triggered by the tumor microenvironment. Overexpression of hydrogen sulfide (H2S) in glioma cells becomes a potential stimulus for activating prodrugs. Herein, a novel H2S responsive agent (SNF) containing amonafide (ANF), a self-immolative linker and a trigger group has been developed for imaging and chemotherapy in living cells. SNF exhibited high selectivity and sensitivity towards H2S and also showed excellent lysosome-targeted capability. The activated SNF could translocate to the nucleus, causing DNA damage and blocking the cell cycle. More mechanistic studies indicated that SNF altered the mitochondrial membrane potential and induced autophagy in human glioblastoma-astrocytoma (U87MG). In addition, 3D multicellular U87MG tumor spheroids were used to further confirm the active drug release and high anti-proliferative activity of SNF. This approach may provide a general strategy for developing H2S-triggered prodrugs for synergic cancer therapy.

Upregulation of Rpn10 promotes tumor progression via activation of the NF-κB pathway in clear cell renal cell carcinoma.

The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis in tumor progression. The proteasome subunit Rpn10 is associated with the progression of several tumor types. However, little is known regarding the role of Rpn10 in clear cell renal cell carcinoma (ccRCC). In this study, we found that overexpression of Rpn10 increased ccRCC cell proliferation, migration, and invasion. Silencing Rpn10 expression resulted in decreased cell proli-feration, migration, and invasion in ccRCC cells. Knockdown of Rpn10 inhibits tumor growth and cell proliferation in vivo. Furthermore, we demonstrated that Rpn10 increased cell proliferation, migration, and invasion via regulation of the nuclear factor kappa B (NF-κB) pathway. Rpn10 directly promoted inhibitor of nuclear factor-kappa B alpha (IκBα) degradation through the UPS. Moreover, we observed that upregulation of Rpn10 or downregulation of IκBα in ccRCC was associated with poor prognosis. We found that the combination of these two parameters was a more powerful predictor of poor prognosis than either parameter alone. Collectively, these findings provide evidence that Rpn10 promotes the progression of ccRCC by regulation of the NF-κB pathways and is a prognostic indicator for patients with ccRCC.

NK3 homeobox 1 (NKX3.1) up-regulates forkhead box O1 expression in hepatocellular carcinoma and thereby suppresses tumor proliferation and invasion.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality in China, and the molecular mechanism of uncontrolled HCC progression remains to be explored. NK3 homeobox 1 (NKX3.1), an androgen-regulated prostate-specific transcription factor, suppresses tumors in prostate cancer, but its role in HCC is unknown, especially in hepatocellular carcinoma. In the present study, the differential expression analyses in HCC tissues and matched adjacent noncancerous liver tissues revealed that NKX3.1 is frequently down-regulated in human primary HCC tissues compared with matched adjacent noncancerous liver tissues. We also noted that NKX3.1 significantly inhibits proliferation and mobility of HCC cells both in vitro and in vivo Furthermore, NKX3.1 overexpression resulted in cell cycle arrest at the G1/S phase via direct binding to the promoter of forkhead box O1 (FOXO1) and up-regulation of expression. Of note, FOXO1 silencing in NKX3.1-overexpressing cells reversed the inhibitory effects of NKX3.1 on HCC cell proliferation and invasion. Consistently, both FOXO1 and NKX3.1 were down-regulated in human HCC tissues, and their expression was significantly and positively correlated with each other. These results suggest that NKX3.1 functions as a tumor suppressor in HCC cells through directly up-regulating FOXO1 expression.

Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway.

Tunicamycin (TM) is an N-linked glycosylation (NLG) inhibitor with strong antitumor activity, the exact underlying molecular mechanism of which remains to be elucidated. In our previous studies, we found that TM reversed drug resistance and improved the efficacy of combination treatments for hepatocellular carcinomas (HCC). Here, we investigated the effects of TM on HCC cell proliferation and migration as well as the mechanism of those effects. Our results showed that TM inhibited cell proliferation and migration as well as induced apoptosis of hepatocellular carcinoma cells. TM inhibited proliferation of HCC cells by inducing cell apoptosis and cell cycle arrest at the G2/M phase. Meanwhile, TM inhibited migration of HCC cells by suppressing CD44s-mediated epithelial-mesenchymal transition (EMT). TM inhibited migration and invasion of HCC cells by decreasing CD44 expression and altering its glycosylation. In addition, CD44s is involved in promoting EMT and is associated with a poor prognosis in HCC patients. Overexpression of CD44s promoted tumor migration and activated phosphorylation of ERK1/2 in HCC cells, whereas TM inhibited CD44s overexpression-associated cell migration. The ability of TM to inhibit cell migration and invasion was enhanced or reversed in CD44s knockdown cells and cells overexpressing CD44s, respectively. The MEK/ERK inhibitor U0126 and TM inhibited hyaluronic acid-induced cell migration in HCC cells. Furthermore, TM inhibited exogenous transforming growth factor beta (TGF-ß)-mediated EMT by an ERK1/2-dependent mechanism and restored the TGF-ß-mediated loss of E-cadherin. In summary, our study provides evidence that TM inhibits proliferation and migration of HCC cells through inhibition of CD44s and the ERK1/2 signaling pathway.

Comparison of Percutaneous Kyphoplasty and Bone Cement-Augmented Short-Segment Pedicle Screw Fixation for Management of Kümmell Disease.

BACKGROUND The purpose of this study was to compare the efficacy of percutaneous kyphoplasty (PKP) and bone cement-augmented short segmental fixation (BCA+SSF) for treating Kümmell disease. MATERIAL AND METHODS Between June 2013 and December 2015, 60 patients were treated with PKP or BCA+SSF. All patients were followed up for 12-36 months. We retrospectively reviewed outcomes, including Oswestry Disability Index (ODI), visual analogue scale (VAS), and kyphotic Cobb angle. RESULTS VAS, ODI, and Cobb angle, measured postoperatively and at the final follow-up, were lower than those measured preoperatively in both groups (P<0.05). VAS, ODI, and Cobb angle measured postoperatively demonstrated no significant differences when compared with those measured at the final follow-up in the PKP group (P>0.05). In the BCA+SSF group, VAS and ODI at the final follow-up were lower than those measured postoperatively (P<0.05), but no significant difference was found in the Cobb angle (P>0.05). The PKP group had better VAS and ODI than the BCA+SSF group, postoperatively (P<0.05). No significant difference was found in VAS and ODI at the final follow-up (P>0.05) or the Cobb angle measured postoperatively and at the final follow-up (P>0.05) between the 2 groups. Operative time, blood loss, and hospital stay in the PKP group were lower than those in the BCA+SSF group (P<0.05). No significant difference was found in complications (P>0.05). CONCLUSIONS PKP patients had better early clinical outcomes, shorter operation times and hospital admission times, and decreased blood loss, but had similar complications, radiographic results, and long-term clinical outcomes compared with BCA+SSF patients.

Bone Cement-Augmented Short-Segment Pedicle Screw Fixation for Kümmell Disease with Spinal Canal Stenosis.

BACKGROUND This study aimed to explore the feasibility and efficacy of bone cement-augmented short-segmental pedicle screw fixation in treating Kümmell disease. MATERIAL AND METHODS From June 2012 to June 2015, 18 patients with Kümmell disease with spinal canal stenosis were enrolled in this study. Each patient was treated with bone cement-augmented short-segment fixation and posterolateral bone grafting, and posterior decompression was performed when needed. All patients were followed up for 12-36 months. We retrospectively reviewed outcomes, including the Oswestry disability index (ODI), visual analog scale (VAS) score, anterior and posterior heights of fractured vertebrae, kyphotic Cobb angle, and neurological function by Frankel classification. RESULTS The VAS grades, ODI scores, anterior heights of affected vertebrae, and kyphotic Cobb angles showed statistically significant differences between pre- and postoperative and between preoperative and final follow-up values (P<0.05), whereas the differences between postoperative and final follow-up values were not statistically significant (P>0.05). The differences between posterior vertebral heights at each time point were not statistically significant (P>0.05). Improved neurological function was observed in 12 cases at final follow-up. Three cases had complications, including asymptomatic cement leakage in 2 patients and delayed wound infection in 1 patient. CONCLUSIONS Bone cement-augmented short-segment pedicle screw fixation is safe and effective for treating Kümmell disease, and can achieve satisfactory correction of kyphosis and vertebral height, with pain relief and improvement in neurological function, with few complications.

Downregulation of AZGP1 by Ikaros and histone deacetylase promotes tumor progression through the PTEN/Akt and CD44s pathways in hepatocellular carcinoma.

Increasing evidence has shown that zinc-alpha2-glycoprotein (AZGP1) is associated with the progression and prognosis of several tumor types. However, little is known regarding the underlying molecular mechanisms of AZGP1 in hepatocellular carcinoma (HCC). In this study, we report that transcription factor Ikaros bound to the AZGP1 promoter and increased its expression in HCC cells. The downregulation of AZGP1 was associated with histone deacetylation in HCC. In addition, the positive feedback regulation via acetylation of histone H4-mediated transactivation of the Ikaros promoter and the Ikaros-mediated transactivation of the acetylation of histone H4 were crucial for regulating AZGP1 expression in HCC cells. Moreover, low serum AZGP1 level in HCC patients was associated with poor prognosis. The ectopic overexpression of AZGP1 or recombinant AZGP1 protein inhibited HCC cell proliferation, migration and invasion in vitro and in vivo, whereas silencing AZGP1 expression resulted in increased cell proliferation, migration and invasion in vitro. In addition, we found that AZGP1 inhibited cell migration and invasion through the regulation of the PTEN/Akt and CD44s pathways. Collectively, our findings revealed the molecular mechanism of AZGP1 expression in HCC, providing new insights into the mechanisms underlying tumor progression.

Synthesis and photocatalytic activity of Pt-ZnO hybrid nanocomposite by solution plasma technology.

In this paper, Pt-ZnO hybrid nanocomposites were prepared by solution plasma technology. X-ray diffraction (XRD) and energy dispersive x-ray analysis (EDX) were used to verify their chemical composition. The size and morphology of the Pt-ZnO hybrid nanocomposites were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). These results indicate that about 2-3 nm Pt nanoparticles (NPs) were synthesized and dispersed on the pyramid-like ZnO (20-60 nm) surface. Photodegradation of Rhodamine B (RhB) demonstrates that the Pt (5 wt%)-ZnO hybrid nanocomposite has better photocatalytic activity than commercial P25 because Pt NPs restrain the photogenerated electron/hole recombination and increase the catalyst activity.

Derivate Isocorydine (d-ICD) Suppresses Migration and Invasion of Hepatocellular Carcinoma Cell by Downregulating ITGA1 Expression.

In our previous studies, we found that isocorydine (ICD) could be a potential antitumor agent in hepatocellular carcinoma (HCC). Derivate isocorydine (d-ICD), a more effective antitumor agent, has been demonstrated to inhibit proliferation and drug resistance in HCC. In order to investigate the potential role of d-ICD on HCC cell migration and its possible mechanism, wound healing assay, trans-well invasion assay, western blot analysis, and qRT-PCR were performed to study the migration and invasion ability of HCC cells as well as relevant molecular alteration following d-ICD treatment. Results indicated that the migration and invasion ability of HCC cells were suppressed when cultured with d-ICD. Meanwhile, the expression level of ITGA1 was markedly reduced. Furthermore, we found that ITGA1 promotes HCC cell migration and invasion in vitro, and that ITGA1 can partly reverse the effect of d-ICD-induced migration and invasion suppression in HCC cells. In addition, dual luciferase reporter assay and chromatin immunoprecipitation assay were used to study the expression regulation of ITGA1, and found that E2F1 directly upregulates ITGA1 expression and d-ICD inhibits E2F1 expression. Taken together, these results reveal that d-ICD inhibits HCC cell migration and invasion may partly by downregulating E2F1/ITGA1 expression.

Total flavones of Abelmoschus manihot improve diabetic nephropathy by inhibiting the iRhom2/TACE signalling pathway activity in rats.

CONTEXT: Total flavones extracted from Abelmoschus manihot L. (Malvaceae) medic (TFA) have been proven clinically effective at improving renal inflammation and glomerular injury in chronic kidney disease (CKD). OBJECTIVE: This study evaluated the function of TFA as an inhibitor of iRhom2/TACE (tumour necrosis factor-α converting enzyme) signalling and investigated its anti-DN (diabetic nephropathy) effects in a DN rat model. MATERIALS AND METHODS: In vitro, cells were treated with 200 µg/mL advanced glycation end products (AGEs), and then co-cultured with 20 µg/mL TFA for 24 h. Real time PCR, western blotting and co-immunoprecipitation assays were performed. In vivo, DN was induced in 8 week old male Sprague-Dawley rats via unilateral nephrectomy and intraperitoneal injection of streptozotocin, then TFA were administered to rats by gavage for 12 weeks at three different doses (300, 135 and 75 mg/kg/d). 4-Phenylbutanoic acid (2.5 mg/kg/d) was used as a positive control. RESULTS: IC50 of TFA is 35.6 µM in HK2 and 39.6 µM in HRMC. TFA treatment (20 µM) inhibited the activation of iRhom2/TACE signalling in cultured cells induced by AGEs. LD50>26 g/kg and ED50=67 mg/kg of TFA in rat by gavage, TFA dose-dependently downregulated the expression of proinflammatory cytokines and exerted anti-inflammatory effects significantly though inhibiting the activation of iRhom2/TACE signalling. DISCUSSION AND CONCLUSIONS: Our results show that TFA could dose-dependently ameliorate renal inflammation by inhibiting the activation of iRhom2/TACE signalling and attenuating ER stress. These results suggest that TFA has potential therapeutic value for the treatment of DN in humans.

Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis.

We have previously demonstrated that isocorydine (ICD) can be served as a potential antitumor agent in hepatocellular carcinoma (HCC). A novel derivate of isocorydine (d-ICD) could significantly improve its anticancer activity in tumors. However, the molecular mechanisms of d-ICD on HCC cells remain to be unclear. In this study, we observed that d-ICD inhibited cell proliferation and induced apoptosis of HCC cells in a concentration-dependent manner. We found d-ICD induced G2/M cycle arrest of HCC cells via DNA damage 45 alpha (GADD45A) and p21 pathway in vitro and in vivo. In d-ICD-treated cells, cell cycle-related proteins cyclin B1 and p-CDC2 were upregulated and p-cyclin B1, CDC2, and E2F1 were inhibited. p21 expression can be reversed by knockdown of GADD45A in d-ICD-treated HCC cells. Enforced expression of CCAAT/enhancer-binding protein ß (C/EBPß) in combination with d-ICD enhanced the p21 expression in HCC cells. Furthermore, the luciferase reporter assay showed that upregulation of GADD45A by C/EBPß was achieved through the increase of GADD45A promoter activity. These findings indicate that d-ICD inhibits cell proliferation and induces cell cycle arrest through activation of C/EBPß-GADD45A-p21 pathway in HCC cells. d-ICD might be a promising chemotherapeutic agent for the treatment of HCC.

The suppressor of cytokine signaling 2 (SOCS2) inhibits tumor metastasis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cause of cancer-related death worldwide, and its incidence continues to increase. However, the mechanism underlying the development and progression of HCC remains unknown. The suppressor of cytokine signaling 2 (SOCS2) is a member of the SOCS family and influences the carcinogenesis of multiple types of tumors, but the biological roles of SOCS2 in HCC remain unclear. In this study, we found that SOCS2 expression was reduced in HCC tissues compared with matched noncancerous liver tissues. Moreover, decreased SOCS2 expression was significantly associated with the presence of intrahepatic metastasis and high histological grade in HCC patients. Colony formation assays and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that overexpression of SOCS2 or knockdown of endogenous SOCS2 did not significantly affect cell proliferation and tumorigenicity in HCC cells in vitro and in vivo. However, SOCS2 overexpression significantly inhibited the migration and invasion of HCC cells in vitro and inhibited metastasis in vivo. Consistent with these findings, the knockdown of endogenous SOCS2 enhanced migration and invasion in HCC cells in vitro. Our study demonstrated that SOCS2 inhibited human HCC metastasis, and SOCS2 might provide a new potential therapeutic strategy for treating HCC.

Downregulation of FOXP1 Inhibits Cell Proliferation in Hepatocellular Carcinoma by Inducing G1/S Phase Cell Cycle Arrest.

Forkhead box P1 (FOXP1) belongs to a family of winged-helix transcription factors that are involved in the processes of cellular proliferation, differentiation, metabolism, and longevity. FOXP1 can affect cell proliferation and migratory ability in hepatocellular carcinoma (HCC) in vitro. However, little is known about the mechanism of FOXP1 in the proliferation of HCC cells. This study aimed to further explore the function of FOXP1 on the proliferation of HCC cells as well as the relevant mechanism involved. Western blot analysis, tumor xenograft models, and flow cytometry analysis were performed to elucidate the function of FOXP1 in the regulation of cell proliferation in human HCC. We observed that silencing FOXP1 significantly suppressed the growth ability of HCC cells both in vitro and in vivo. In addition, knockdown of FOXP1 induced G1/S phase arrest, and the expression of total and phosphorylated Rb (active type) as well as the levels of E2F1 were markedly decreased at 24 h; however, other proteins, including cyclin-dependent kinase (CDK) 4 and 6 and cyclin D1 did not show noticeable changes. In conclusion, downregulation of FOXP1 inhibits cell proliferation in hepatocellular carcinoma by inducing G1/S phase cell cycle arrest, and the decrease in phosphorylated Rb is the main contributor to this G1/S phase arrest.