Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

A Comparative Study of Seminars Combined with Case-Based Learning versus Lecture-Based Learning for Cancer Pain Teaching in Medical Oncology Internship.

PURPOSE: To determine whether the teaching method of seminars combined with case-based learning (CBL) is superior to the traditional lecture-based learning (LBL) for teaching cancer pain in medical oncology internship. METHODS: Sixty medical and nursing interns in the medical oncology department of our hospital were selected between January 2019 and December 2020. Thirty students received traditional LBL instruction as the control group, and 30 students received combined seminars and CBL instruction as the observation group. The teaching evaluation and assessment was performed by theoretical and practical examinations and questionnaires. RESULTS: In the after-class examination, case analysis, clinical practice and overall scores of the observation group were higher than those of the control group (all p < 0.001). Theoretical knowledge scores did not differ significantly between the two groups (p = 0.470). In the questionnaire regarding attitudes towards opioid use, the observation group had better perceptions of using opioids than the control group (all p < 0.01). In the meantime, students in the observation group outperformed the control group in four aspects: self-learning (p < 0.001), analytical and problem-solving (p < 0.001), clinical thinking (p = 0.001), and clinical practice (p = 0.002) abilities all improved, while stimulating learning interest (p = 0.184) and enhancing theoretical knowledge mastery (p = 0.221) were not significantly different from those of the control group. Overall, students in the observation group were more satisfied with the teaching, teaching methods and teacher performances than the control group (all p < 0.001). CONCLUSION: Compared to the LBL, the combination of seminars and CBL is a more effective teaching method for cancer pain management, which is worth further study.

High STRN Expression Promotes HCC Invasion and Migration but Not Cell Proliferation or Apoptosis through Facilitating Epithelial-Mesenchymal Transition.

A STRN-ALK fusion protein has been recently identified as a potential therapeutic target in multiple cancers; however, the role of STRN alone in regulating the biological function of hepatocellular carcinoma (HCC) remains unclear. In this study, we firstly detected an overexpression of STRN in HCC tissues compared to that in adjacent nontumour (ANT) tissues through IHC analysis, and the expression level of this protein was positively correlated with lymph node metastasis and TNM stage. In vitro, high expression of STRN was also confirmed in different HCC cell lines, and regulation of STRN expression in Huh7 cells did not significantly affect tumour cell proliferation or apoptosis but was positively correlated with tumour cell invasion and migration capacities. Moreover, both the knockdown and overexpression of STRN in Huh7 cells can lead to cell morphological changes that are accompanied with an alteration of epithelial-mesenchymal transition (EMT) molecular markers E-cadherin and Vimentin. Finally, STRN was further proved to be negatively related to E-cadherin expression but positively related to Vimentin expression in human HCC tissue samples. Taken together, STRN is upregulated in HCC and acts as a tumour promoter regulating cell invasion and migration through facilitating the EMT process.

Over-expression of Thrombospondin 4 correlates with loss of miR-142 and contributes to migration and vascular invasion of advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy found worldwide and is associated with a high incidence of metastasis and vascular invasion. Elucidating the molecular mechanisms that underlie HCC tumorigenesis and progression is necessary for the development of novel therapeutics. By analyzing the Cancer Genome Atlas Network (TCGA) dataset, we identified Thrombospondin 4 (THBS4) is significantly overexpressed in HCC samples and is correlated with prognosis. Overexpression of THBS4 was also highly correlated with vascular invasion of advanced HCC. While THBS4 is often overexpressed in HCC it has also been shown to inhibit tumor growth by mediating cell-to-cell and cell-to-matrix interactions. Here, we identified that knockdown of THBS4 inhibits migration and invasion of HCC cells and inhibits HCC induced angiogenesis. MiRNAs are crucial regulators of multiple cellular processes, and aberrant expression of miRNAs has been observed to effect cancer development and progression. We further found that miR-142 is an upstream regulator of THBS4 in HCC cells. Moreover, miR-142 was significantly down-regulated in HCC tissue samples and correlated with overexpression of THBS4. Overexpression of miR-142 inhibited invasion and angiogenesis of HCC cells and re-expression of THBS4 overcame these effects of miR-142 expression. Stable over-expression of miR-142 significantly inhibited tumour growth in a xenograft tumour model through inhibiting THBS4 expression and tumor angiogenesis. In conclusion, our findings indicate that loss of miR-142 results in the over-expression of THBS4, which enhances HCC migration and vascular invasion. Thus, targeting THBS4 or miR-142 may provide a promising therapeutic strategy for treatment of advanced HCC.

MiR-130a-3p regulates cell migration and invasion via inhibition of Smad4 in gemcitabine resistant hepatoma cells.

BACKGROUND: Emerging evidence demonstrates that microRNAs (miRNAs) play an important role in regulation of cell growth, invasion and metastasis through inhibiting the expression of their targets. It has been reported that miR-130a-3p controls cell growth, migration and invasion in a variety of cancer cells. However, it is unclear whether miR-130a-3p regulates epithelial-mesenchymal transition (EMT) in drug resistant cancer cells. Therefore, in the current study, we explore the role and molecular mechanisms of miR-130a-3p in gemcitabine resistant (GR) hepatocellular carcinoma (HCC) cells. METHODS: The real-time RT-PCR was used to measure the miR-130a-3p expression in GR HCC cells compared with their parental cells. The wound healing assay was conducted to determine the cell migratory activity in GR HCC cells treated with miR-130a-3p mimics. The migration and invasion assays were also performed to explore the role of miR-130a-3p in GR HCC cells. Western blotting analysis was used to measure the expression of Smad4, E-cadherin, Vimentin, and MMP-2 in GR HCC cells after depletion of Smad4. The luciferase assay was conducted to validate whether Smad4 is a target of miR-130a-3p. The student t-test was used to analyze our data. RESULTS: We found the down-regulation of miR-130a-3p in GR HCC cells. Moreover, we validate the Smad4 as a potential target of miR-130a-3p. Furthermore, overexpression of miR-130a-3p suppressed Smad4 expression, whereas inhibition of miR-130a-3p increased Smad4 expression. Consistently, overexpression of miR-130a-3p or down-regulation of Smad4 suppressed the cell detachment, attachment, migration, and invasion in GR HCC cells. CONCLUSIONS: Our findings provide a molecular insight on understanding drug resistance in HCC cells. Therefore, activation of miR-130a-3p or inactivation of Smad4 could be a novel approach for the treatment of HCC.

Impaired gap junctions in human hepatocellular carcinoma limit intrinsic oxaliplatin chemosensitivity: A key role of connexin 26.

Hepatocellular carcinoma (HCC) is generally believed to have low sensitivity to chemotherapeutic agents including oxaliplatin (OXA). Studies have demonstrated that gap junctions (GJs) composed of connexin (Cx) proteins have the potential to modulate drug chemosensitivity in multiple tumor cells. In the present study, we investigated the characteristics of Cx and GJs in HCC at both histologic and cytologic levels, and the effects of GJ and its effective components on OXA cytotoxicity in HCC cells in vitro. Immunohistochemistry was performed in 76 HCCs and 20 normal liver tissues to detect and locate the expression of Cx26, Cx32 and Cx43. At cytologic levels, the expression and localization of Cxs were evaluated by RT-PCR, western blot and immunofluorescence assay, respectively. The GJ function between adjacent cells was detected using dye transfer assay. The role of GJs in the modulation of OXA toxicity in HCC cells was explored using pharmacologic and molecular biologic methods. We found that Cx expression in HCC tissues was significantly lower than in normal liver tissues, and the 'internalization' from cell membrane to cytoplasm was remarkable. In vitro experiments revealed the presence of functional GJs in the SMMC-7721 HCC cells due to a small amount of Cx protein along the plasma membrane at cell-cell contacts. Regulation of this part of GJs positively influenced OXA cytotoxicity. Using RNA interference, only specific inhibition of Cx26 but not Cx32 or Cx43 reduced OXA cytotoxicity. Conversely, Cx26 overexpression by transfection of Cx26 plasmid DNA enhanced OXA cytotoxicity. This study demonstrated that during hepatocarcinogenesis, the reduced expression and internalization of Cx proteins impaired the GJ function, which further attenuated OXA cytotoxicity. Impaired GJ function may contribute to low intrinsic chemosensitivity of HCC cells to OXA, mediated by Cx26.

Programmed cell death 1 correlates with the occurrence and development of MG63 osteosarcoma.

The aim of the present study was to investigate the effect of programmed cell death 1 (PD-1) on osteosarcoma (OD) stem cells and T cells, and to determine their correlation. OS stem cells were sorted and identified from OS MG63 cells. Flow cytometry was used to detect the PD-1 expression of the OS tumor stem cell membrane surface. The expression of PD-1 mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). MTT was used to detect the effect of PD-1 signals on T-cell proliferation. The results indicated that the cancer cells (cultured in DMEM medium containing 10% fetal bovine serum) exhibited clear proliferation within 1 week of cell culture, which showed their strong proliferation and aggressive ability. The formation of tumor cell spheres was dependent on the support of serum nutrition. The proliferation of MG63 cells in the serum culture medium was significantly higher than the number of OS cell spheres in serum-free suspension culture (P<0.05). Pluripotent stem cells in cancer cell spheres exhibited significantly higher cluster of differentiation 133 expression compared with the MG63 cells. The PD-1 expression levels of the cancer cell spheres was significantly increased compared with the MG63 cells, which is consistent with the results of the RT-PCR. In conclusion, the MG63 cell line possesses the features of OS stem cells. The MG63 cell line can express the certain cancer-associated cell markers. The expression of PD-1 in spheres was also increased significantly compared to the MG63 cells, which can reduce the immune function of patients and may be closely associated with the occurrence and development of tumors.

[Expression of gap junction protein connexin 26 in human hepatocellular carcinoma and its significance].

OBJECTIVE: To investigate the expression of gap junction protein connexin 26(Cx26) in hepatocellular carcinoma(HCC) and its significance. METHODS: The expression of Cx26 in liver tissue was examined by immunohistochemistry staining in 159 paraffin-embeded liver sections, including 20 samples of normal liver tissue, 30 samples of chronic hepatitis, 33 samples of liver cirrhosis, and 76 samples of HCC. Normal hepatic cell line LO2 and HCC cell line SMMC-7721 were used in vitro to verify the characteristics of gap junction and Cx26 expression pattern. The expression and localization of Cx26 were measured by Western blotting and immunofluorescence assay, respectively. The function of gap junction between adjacent cells was detected by dye transfer assay. RESULTS: Compared to normal liver samples, the positive rate of Cx26 was markedly decreased in hepatitis, cirrhosis and HCC tissues(all P<0.05). The intensity of Cx26 staining was significantly increased in HCC tissues compared with those in non-carcinomatous liver(NCL) tissues(all P<0.05). In NCL tissues, there was a mild to moderated staining of Cx26 which located mainly on the membranes of hepatocytes at intercellular contacts. The positive staining of Cx26 in HCC tissues was observed mainly in cytoplasm. Positive Cx26 expression was positively associated with tumor size(P=0.036), but not with age, gender, histologic grade, clinical stage, underlying hepatitis and cirhosis, lymph node metastasis and intrahepatic vascular embolism(all P>0.05). Compared with LO2 cells, an aberrant expression and distribution of Cx26 in SMMC-7721 cells was confirmed, which may lead to a decreased function of gap junctions. CONCLUSIONS: The aberrant expression and distribution of Cx26 protein may be associated with hepatocarcinogenesis, and the residual gap junction in HCC may provide a new target for treatment of HCC.

[Correlation of triggering receptors expressed on myeloid cells-1 with the oncogenesis and progression of hepatocellular carcinoma].

OBJECTIVE: To investigate the role of triggering receptors expressed on myeloid cells-1 (TREM-1) in the oncogenesis and progression of hepatocellular carcinoma (HCC). METHODS: The expression and localization of TREM-1 were detected by immunohistochemistry in 76 specimens of HCC, 33 specimens of liver cirrhosis, 30 specimens of hepatitis and 20 normal liver tissues. The association between TREM-1 expression and the clinicopathologic parameters of HCC was analyzed. Human normal hepatic cell line LO2 and HCC cell line SMMC-7721 were examined for TREM-1 expression pattern using RT-PCR and Western blotting. RESULTS: All the normal liver samples showed negative expression of TREM-1 protein, which was significantly up-regulated in the other 3 tissues. The positivity rates of TREM-1 expression were not significantly different between hepatitis, cirrhosis and HCC tissues [20.00% (6/30), 24.24% (8/33), and 21.05% (16/76), respectively; Χ² =0.195, P=0.907]. Different from chronic hepatitis and liver cirrhosis tissues where TREM-1 expression was located mainly in the nucleus and occasionally in the cytoplasm of the hepatocytes, HCC tissues showed a cellular localization of TREM-1 protein almost exclusively in the cytoplasm. In HCC, TREM-1 expression was negatively correlated with the histological grade of the tumor (r=-0.261, P=0.023) but not related with the patients' age, gender, tumor size, clinical stage, pre-existing hepatitis and cirrhosis, lymph node metastasis, or intrahepatic vascular embolism (all P>0.05). In the in vitro experiments, low levels of TREM-1 mRNA and protein expressions were detected in LO2 cells line, but their expressions were markedly up-regulated in SMMC-7721 cells. CONCLUSION: Aberrant enhancement of the expression and cytoplasmic accumulation of TREM-1 may correlate closely with the oncogenesis and progression of HCC.

MiRNA profile of osteosarcoma with CD117 and stro-1 expression: miR-1247 functions as an onco-miRNA by targeting MAP3K9.

microRNAs (miRNA) are regulators of gene expression, but little is known about miRNA expression profiles in stem cells of osteosarcoma (OS). C117 and Stro-1 are known stem cell markers of OS. In the study, CD117 and stro-1 positive (CD117(+)stro-1(+)) and CD117 and stro-1 negative (CD117(-)stro-1(-)) cells were isolated from MG63 cells CD117(+)stro-1(+) cells showed more metastatic ability and stem cell formation rate than CD117(-)stro-1(-) ones. To find the difference between CD117(+)stro-1(+) and CD117(-)stro-1(-) cells, the miRNA expression profile was examined using DNA microarray. MicroRNAs were differentially expressed in osteosarcoma cells with CD117(+)stro-1(+) and CD117(-)stro-1(-). The significant miRNAs included miR-15a, miR-302a, miR-423-5p, miR-1247, miR-1243 and others, which were confirmed by real time RT-PCR. The significant down-regulated miR-1247 was confirmed that was a potential tumor suppressor by targeting MAP3K9. Our results indicated that dysregulation of miRNAs is involved in osteosarcoma and miR-1247 plays an important role in progression of osteosarcoma.

Prognostic value of CD117 in cancer: a meta-analysis.

BACKGROUND: The prognostic value of CD117 expression in cancers has been evaluated for several years while the results remain controversial. We thus performed a systematic review and meta-analysis of studies assessing the impact of CD117 expression on overall survival (OS) and disease-free survival (DFS) to clarify this issue. METHODS: We searched Pubmed, Embase and Web of Science to identify studies on the prognostic impact of CD117 expression in cancers. A total of 4,458 patients from 39 eligible studies were included in the analysis. Pooled risk ratios (RRs) with 95% confidence interval (95% CI) were calculated to estimate the effect using random-effects model. RESULTS: The analysis indicated that CD117 had significant association with poor OS of osteosarcoma (OR=1.36, 95% CI=1.03-1.79, I2=0%, fixed model) and renal carcinoma (OR=4.86, 95% CI=2.72-8.67, I2=0%, fixed model).However, no significant association between CD117 and DFS was found in overall studies. CONCLUSIONS: CD117 expression might be a predictive factor of poor prognosis in some surgically treated cancers, particularly in renal carcinoma.