GLIPR1 promotes proliferation, metastasis and 5-fluorouracil resistance in hepatocellular carcinoma by activating the PI3K/PDK1/ROCK1 pathway.

Hepatocellular carcinoma (HCC) contributes to a heavy disease burden for its high prevalence and poor prognosis, with limited effective systemic therapies available. In the era of precision medicine, treatment efficacy might be improved by combining personalized systemic therapies. Since oncogenic activation is one of the primary driving forces in HCC, characterization of these oncogenes can provide insights for developing new targeted therapies. Based on RNA sequencing of epithelial-mesenchymal transition (EMT)-induced HCC cells, this study discovers and characterizes glioma pathogenesis-related protein 1 (GLIPR1) that robustly drives HCC progression and can potentially serve as a prognostic biomarker and therapeutic target with clinical utility. GLIPR1 serves opposing roles and involves distinct mechanisms in different cancers. However, based on integrated in-silico analysis, in vitro and in vivo functional investigations, we demonstrate that GLIPR1 plays a multi-faceted oncogenic role in HCC development via enhancing tumor proliferation, metastasis, and 5FU resistance. We also found that GLIPR1 induces EMT and is actively involved in the PI3K/PDK1/ROCK1 singling axis to exert its oncogenic effects. Thus, pre-clinical evaluation of GLIPR1 and its downstream factors in HCC patients might facilitate further discovery of therapeutic targets, as well as improve HCC chemotherapeutic outcomes and prognosis.

External Validation of a Nomogram to Predict Survival and Benefit of Concurrent Chemoradiation for Stage II Nasopharyngeal Carcinoma.

A nomogram was recently published by Sun et al. to predict overall survival (OS) and the additional benefit of concurrent chemoradiation (CCRT) vs. radiotherapy (RT) alone, in stage II NPC treated with conventional RT. We aimed to assess the predictors of OS and to externally validate the nomogram in the IMRT era. We analyzed stage II NPC patients treated with definitive RT alone or CCRT between 2001 and 2011 under the territory-wide Hong Kong NPC Study Group 1301 study. Clinical parameters were studied using the Cox proportional hazards model to estimate OS. The nomogram by Sun et al. was applied with 1000 times bootstrap resampling to calculate the concordance index, and we compared the nomogram predicted and observed 5-year OS. There were 482 patients included. The 5-year OS was 89.0%. In the multivariable analysis, an age > 45 years was the only significant predictor of OS (HR, 1.98; 95%CI, 1.15-3.44). Other clinical parameters were insignificant, including the use of CCRT (HR, 0.99; 95%CI, 0.62-1.58). The nomogram yielded a concordance index of 0.55 (95% CI, 0.49-0.62) which lacked clinically meaningful discriminative power. The nomogram proposed by Sun et al. should be interpreted with caution when applied to stage II NPC patients in the IMRT era. The benefit of CCRT remained controversial.

Role of MIF/CXCL8/CXCR2 signaling in the growth of nasopharyngeal carcinoma tumor spheres.

Macrophage migration inhibitory factor (MIF) and CXCL8 (also named IL-8) are strongly expressed in the tissues of nasopharyngeal carcinoma (NPC). However, their role in the growth of NPC has not been fully examined. This study aims to evaluate the functions of MIF and CXCL8 on the growth of NPC tumor spheres. The elevated expression of CXCL8 in tumor over normal tissues was confirmed in 37 pairs of biopsies from NPC patients. In the in vitro study, all the poorly differentiated NPC cell lines, including the EBV-positive C666-1, and the EBV-negative CNE-1, CNE-2, SUNE-1, HNE-1 and HONE-1 cells, were found to express CXCL8 and MIF. Therefore, the EBV-positive C666-1 cell was selected to examine for the role of MIF and CXCL8 in the growth of the NPC tumor spheres. Functional study showed that the growth of C666-1 tumor spheres, under the nutrient poor or growth factor supplemented culture conditions, could be inhibited by the CXCL8 specific peptide inhibitor. The growth of the tumor spheres could also be reduced by the CXCR2 specific inhibitor SB225002 or the PI3K/AKT inhibitor LY294002, indicating that the endogenously produced CXCL8 plays an autocrine role in the growth of the tumor spheres. Further mechanistic studies revealed that the gene expression of CXCL8 could be reduced by the MIF specific small interfering RNA (siRNA) or NF-κB inhibitor parthenolide, and the growth of tumor spheres was also reduced after MIF siRNA transfection. Taken together, the present study highlights the role of MIF/CXCL8/CXCR2 axis in the growth of NPC tumor spheres. Chemotherapeutic interference of this signaling pathway may help to control the growth of the NPC tumor.

Effectiveness of brachytherapy and fractionated stereotactic radiotherapy boost for persistent nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) with local persistence after primary radiotherapy carries a high risk of treatment failure. We compared the effectiveness of brachytherapy and a fractionated stereotactic radiotherapy (SRT) boost in improving tumor control. METHODS: We retrospectively reviewed the records of 755 patients with NPC treated from 1994 to 2001. Fifty-two patients (7%) had persistent local disease, but seven of them were unsuitable for radiotherapy boost. Overall, 24 patients received brachytherapy boost at a median dose of 20 Gy, and 21 patients received an SRT boost at a median dose of 15 Gy. RESULTS: Despite the radiotherapy boost, the overall 3-year local failure-free control rate was still significantly lower for patients with persistent disease than for the rest (71% vs 86%, p < .01). Only the SRT subgroup achieved a local failure-free control rate close to that of the complete responders (82% vs 86%, p = .71). CONCLUSIONS: SRT boost is more effective in reverting the poor prognostic influence of local persistent disease.