Our findings indicate that the CD147-CD98hc complex significantly contributes to poor prognosis of NSCLC patients through promoting cell proliferation via the PI3K/Akt pathway.

Hypoxia-inducible factor 1α (HIF-1α) plays an important role in tumor growth and metastasis. Genetic variations of HIF1A gene have been shown to influence the developing risk and prognosis in many types of human malignancies. However, their association with clinical outcomes of hepatocellular carcinoma (HCC) patients remains unclear. To investigate the predictive role of single nucleotide polymorphisms (SNPs) in HIF1A gene in HCC patients’ outcomes, we genotyped three functional SNPs (rs2057482, rs1957757 and rs2301113) in HIF1A gene and assessed their associations with clinicopathological parameters and prognosis of 492 surgical HCC patients. The patients with variant alleles (CT+TT) of SNP rs2057482 had a significantly lower recurrence risk when compared with patients with the CC genotype. In stratified analysis, the protective effect of rs2057482 CT+TT genotype was more evident in patients with adverse strata, compared with patients with favorable strata. Additionally, strong joint predictive effect between rs2057482 genotypes and AFP level, stage or differentiation were observed. Functional assay also indicated the significant effect of rs2057482 on gene expression. In conclusion, SNP rs2057482 in HIF1A gene is significantly associated with clinical outcomes of Chinese HCC patients after surgery, especially in those with aggressive status, which warrants further validation in other patient populations.

Recent studies have revealed significant intratumor heterogeneity (ITH) of nuclear genome mutations and highlighted its function in tumor progression and treatment resistance. However, the ITH of somatic mitochondrial DNA (mtDNA) mutations detected in cancers remains unknown. In this study, we performed multiregional mtDNA sequencing of tumor and paratumor tissue samples from 12 hepatocellular carcinoma (HCC) and 13 colorectal cancer (CRC) patients. A substantial level of mtDNA mutations was found in paired non-HCC inflammatory tissues, suggesting that these tissues might not be mtDNA-genetically "normal." Moreover, our data indicated that the ITH of somatic mtDNA mutations was a common feature in HCC and CRC patients. In addition, we found that shared mutations which were observed in at least 2 samples in each patient exhibited a significantly higher heteroplasmic level than mutations that were private to a specific tumor region from both HCC (p = 0.039) and CRC patients (p = 0.001). The heteroplasmic level of shared mutations was positively correlated with intratumoral recurrence of mtDNA mutations. We also found that shared mutations in tumor tissues with a higher degree of pathogenicity risk exhibited a higher heteroplasmic level and intratumoral recurrence in both HCC and CRC patients. These findings suggest that some mtDNA mutations may undergo positive selection during the clonal expansion. Taken together, our analyses identified various levels of ITH of somatic mtDNA mutations in HCC and CRC patients and provided evidence supporting the positive selection working on some somatic mtDNA mutations in tumor tissues.

BackgroundTumor necrosis factor-α has been proven an effective anticancer agent in preclinical studies. However, the translation of TNFα from research to clinic has been blocked by significant systemic toxicity and limited efficacy at maximal tolerated dose, which need urgently to be solved.MethodsThe level of cytosolic Ca2+ was assessed by Fura-2 in HCC cells. After changing cytosolic Ca2+ level by using agonists or inhibitors, cell apoptosis was detected by flow cytometry. We also detected the effect of ionomycin or parvalbumin on the anti-tumor activity of TNFα in a mice model. Lastly, we studied the roles of cytosolic Ca2+ in the mitochondrial-dependent intrinsic apoptosis pathway.ResultsHere, we demonstrated that TNFα induced extracellular Ca2+ influx into cytoplasm through transient receptor potential channel in HCC cells. Both cytosolic Ca2+ scavenger and Ca2+-binding protein PV effectively desensitized hepatocellular carcinoma cells to TNFα, whereas combination ionomycin or 1,4,5-inositol triphosphate significantly sensitized HCC cells to TNFα, indicating that the increased level of cytosolic Ca2+ was positively correlated with the TNFα-induced cell apoptosis in vitro. In a nude mice xenograft model, our data revealed that TNFα combined with ionomycin remarkably synergized the anti-tumor effect of TNFα. Furthermore, we found that TNFα-mediated extracellular Ca2+ influx accelerated TNFα-induced extrinsic apoptosis through activating calpain/IAP/caspase3 pathway.ConclusionsOur study provides the evidence supporting a novel mechanism by which TNFα induces extracellular Ca2+ influx to enhance cell apoptosis and suggests that increasing the level of cytosolic Ca2+ might be an alternative strategy to improve the pro-apoptotic activity of TNFα in HCC cells, although suitable chemical or biological reagents need to be further tested.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0714-6) contains supplementary material, which is available to authorized users.

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