Liver X receptors agonist T0901317 exerts ferroptosis sensitization in cancer.

Numerous studies have confirmed the anticancer effects of ferroptosis on a wide range of tumors, specifically in providing new perspectives for tackling drug resistance and treating refractory tumors. Notably, mechanisms of improving tumor susceptibility to ferroptosis have been a focus of current research. This study discovered that co-treatment of LXRS agonist T0901317 and ferroptosis inducers (FINs) significantly inhibited the proliferation of cancer cells, this inhibition effect could be reversed by specific inhibitors of ferroptosis and accompanied by elevated lipid peroxides. Glutathione peroxidase 4 (GPX4) regulates T0901317 induced ferroptotic sensitization, and its overexpression dramatically reverses the joint anticancer effect of T0901317 and FINs. Furthermore, xenograft model results highly confirmed the ferroptotic sensitization effect of T0901317 in vivo. In summary, our findings indicate that drug combination and ferroptosis induction strategies provide novel options for cancer therapy.

iASPP-Mediated ROS Inhibition Drives 5-Fu Resistance Dependent on Nrf2 Antioxidative Signaling Pathway in Gastric Adenocarcinoma.

AIMS: Inhibitor for the apoptosis-stimulating protein of p53 (iASPP) has been reported to be correlated with 5-fluorouracil (5-Fu) resistance in renal cell carcinoma. Here, we uncover mechanisms of iASPP-Nrf2-ROS regulation of 5-Fu resistance which are important for the development of alternative treatment strategies for gastric adenocarcinoma treatment. METHODS: We analyzed iASPP and Nrf2 through TCGA RNA-seq data, UALCAN analysis, and cBioPortal datasets. Intracellular ROS generation was determined by 2',7'-dichloro-fluorescin diacetate staining. Transwell was used to evaluate the invasion. The expression of iASPP, Nrf2, HO-1, and GSTP1 was tested using western blot. RESULTS: We found that iASPP KD led to an apparent 5-Fu-induced ROS accumulation in MGC803 and SCG790 cells. Accompanied by iASPP KD, Nrf2 was markedly decreased. iASPP-induced ROS inhibition relies on Nrf2, and due to both knocked down iASPP and Nrf2, the level of ROS did not show an obvious difference with Nrf2 KD solely. Similarly, iASPP KD failed to enhance the Nrf2 KD-mediated ROS accumulation after 5-Fu treatment, suggesting that iASPP-induced antioxidative effects related to 5-Fu resistance are partially dependent on Nrf2. Also, the combination of iASPP KD and Nrf2 KD did not show any synergistic effect on apoptosis after 5-Fu treatment in MGC803 and SCG790 cells. Further studies revealed that iASPP KD or Nrf2 KD could decrease the expression of HO-1 and GSTP1. CONCLUSIONS: Our data highlight that iASPP plays a crucial role in the inhibition of 5-Fu-induced apoptosis resistance by removing ROS accumulation in gastric adenocarcinoma, and that the removal of ROS induced by iASPP is Nrf2 signaling dependent.

Prognostic impact of tumor mutation burden and the mutation in KIAA1211 in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive lung cancer subtype with poor survival and limited treatment options. Sequencing results have revealed gene mutations associated with SCLC, however, the correlation between the genomic alterations and clinical prognosis of SCLC is yet unclear. METHODS: Targeted next-generation sequencing of 62 cancer related genes was performed on 53 SCLC samples. The correlations between clinical outcomes and genomic alterations were analyzed. RESULTS: 38/62 (61.3%) candidate genes harbored some alterations, while all the SCLC samples carried at least 3 gene mutations. The most common nonsynonymous mutations included ERBB2 (95.9%), CREBBP (95.9%), and TP53 (77.6%). The median nonsynonymous tumor mutation burden (TMB) was 21.7 mutations/Mb (rang, 9.3-55.9). High TMB (> 21 mutations/Mb) was good prognostic factor in overall survival (OS) (21.7 vs. 10.4 months, P = 0.012). Multivariate analysis showed that high TMB was an independent prognostic factor. The overall survival (OS) of patients carrying KIAA1211 mutation was significantly longer than those with wild-type KIAA1211 (P < 0.001). CONCLUSIONS: The current study highlights the potential role of genomic alterations for the prognosis of SCLC. Higher TMB was associated with a better prognosis, and KIAA1211 might be a good prognostic factor in SCLC.

GPX2 overexpression indicates poor prognosis in patients with hepatocellular carcinoma.

Glutathione peroxidase 2 has important role of tumor progression in lots of carcinomas, yet little is known about the prognosis of glutathione peroxidase 2 in hepatocellular carcinoma. Glutathione peroxidase 2 expression was assessed by immunohistochemistry in hepatocellular carcinoma tissues. The association between glutathione peroxidase 2 expression with clinicopathological/prognostic value was examined. Glutathione peroxidase 2 overexpression was correlated with alpha-fetoprotein level, larger tumor, BCLC stage, and tumor recurrence. Kaplan-Meier analysis showed that glutathione peroxidase 2 was an independent predictor for overall survival and time to recurrence. glutathione peroxidase 2 overexpression was correlated with poor prognosis in patient subgroups stratified by tumor size, differentiation, tumor-node-metastasis, and BCLC stage. Moreover, stratified analysis showed that tumor-node-metastasis stage-I patients with high glutathione peroxidase 2 expression had poor prognosis than those with low glutathione peroxidase 2 expression. Additionally, combination of glutathione peroxidase 2 and serum alpha-fetoprotein was correlated with prognosis in hepatocellular carcinoma. In conclusion, glutathione peroxidase 2 overexpression contributes to poor prognosis of hepatocellular carcinoma patients and helps to identify the high-risk hepatocellular carcinoma patients.

Increased expression of SHP-1 is associated with local recurrence after radiotherapy in patients with nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a major cancer in southern China. Src homology phosphatase-1 (SHP-1) is a tyrosine phosphatase that regulates growth, differentiation, cell cycle progression, and oncogenesis. We determined the clinical significance of SHP-1 expression in the tumours of NPC patients from southern China who were treated with radiotherapy. PATIENTS AND METHODS: SHP-1 expression was determined by real-time polymerase chain reaction (PCR) and western blotting of NPC tissue samples of 50 patients and nasopharyngeal tissues of 50 non-NPC patients who had chronic nasopharyngeal inflammation. SHP-1 expression was measured in NPC tissue samples of 206 patients by immunohistochemistry and survival analysis was performed. RESULTS: The tumours of NPC patients had significantly increased expression of SHP-1 at mRNA and protein levels relative to patients with chronic nasopharyngeal inflammation. Survival analysis of NPC patients indicated that SHP-1 expression was significantly associated with poor local recurrence-free survival (p = 0.008), but not with nodal recurrence-free survival, distant metastasis-free survival, or overall survival. CONCLUSIONS: SHP-1 appears to be associated with radiation resistance of NPC cells and can be considered as a candidate marker for prognosis and/or therapeutic target in patients with this type of cancer.

Factors associated with HPV vaccine hesitancy among college students: A cross-sectional survey based on 3Cs and structural equation model in China.

Despite the high effectiveness of HPV vaccines in preventing infection, vaccine hesitancy remains a concern, particularly in China. This study aimed to explore college students' attitudes toward HPV vaccination and identify associated factors. Data was collected through a cross-sectional survey using self-administered questionnaires in four cities from May to June 2022. Chi-square tests and logistic regression analyses were conducted to identify factors. Additionally, an integrated structural equation model (SEM) based on the 3Cs (confidence, convenience, complacency) was developed to understand underlying factors contributing to hesitancy. The results from 2261 valid questionnaires were enlightening. A significant 89.47% (59.4% for females) considered HPV vaccination necessary, with 9.82% remaining neutral and only 0.71% deeming it unnecessary. Factors like higher education, being a medical student, residing in urban areas, having medical insurance, more extraordinary living expenses, a family history of tumors, and a solid understanding of HPV played a role in perceiving the vaccine as necessary. Among the 1438 female respondents, 84.36% had no hesitancy toward HPV vaccination, 13.53% expressed hesitancy, and 2.11% refused vaccination. Factors like age, understanding of HPV, medical staff recommendations, living expenses, and family history influenced hesitancy levels. SEM revealed that the 3Cs significantly affected vaccine hesitancy. Factors like price, booking process, vaccination times, trust in vaccines, medical staff recommendations, efficiency, and risk perception collectively influenced hesitancy. In conclusion, this study found high acceptance of HPV vaccination but acknowledged the complexity of hesitancy factors. It recommends medical staff disseminate scientific knowledge, offer recommendations, simplify booking procedures, and expand vaccination sites to address vaccine hesitancy effectively.

Deficiency of Carbamoyl Phosphate Synthetase 1 Engenders Radioresistance in Hepatocellular Carcinoma via Deubiquitinating c-Myc.

PURPOSE: Tumor radiation resistance is the main obstacle to effective radiation therapy for patients with hepatocellular carcinoma (HCC). We identified the role of urea cycle key enzyme carbamoyl phosphate synthetase 1 (CPS1) in radioresistance of HCC and explored its mechanism, aiming to provide a novel radiosensitization strategy for the CPS1-deficiency HCC subtype. METHODS AND MATERIALS: The expression of CPS1 was measured by western blot and immunohistochemistry. Cell growth assay, EdU assay, cell apoptosis assay, cell cycle assay, clone formation assay, and subcutaneous tumor assay were performed to explore the relationship between CPS1 and radioresistance of HCC cells. Lipid metabonomic analysis was used for investigating the effects of CPS1 on lipid synthesis of HCC cells. RNA sequencing and coimmunoprecipitation assay were carried out to reveal the mechanism of CPS1 participating in the regulation of HCC radiation therapy resistance. Furthermore, 10074-G5, the specific inhibitor of c-Myc, was administered to HCC cells to investigate the role of c-Myc in CPS1-deficiency HCC cells. RESULTS: We found that urea cycle key enzyme CPS1 was frequently lower in human HCC samples and positively associated with the patient's prognosis. Functionally, the present study proved that CPS1 depletion could accelerate the development of HCC and induce radiation resistance of HCC in vitro and in vivo, and deficiency of CPS1 promoted the synthesis of some lipid molecules. Regarding the mechanism, we uncovered that inhibition of CPS1 upregulated CyclinA2 and CyclinD1 by stabilizing oncoprotein c-Myc at the posttranscriptional level and generated radioresistance of HCC cells. Moreover, inactivation of c-Myc using 10074-G5, a specific c-Myc inhibitor, could partially attenuate the proliferation and radioresistance induced by depletion of CPS1. CONCLUSIONS: Our results recapitulated that silencing CPS1 could promote HCC progression and radioresistance via c-Myc stability mediated by the ubiquitin-proteasome system, suggesting that targeting c-Myc in CPS1-deficiency HCC subtype may be a valuable radiosensitization strategy in the treatment of HCC.

Corrigendum to "Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis".

[This corrects the article DOI: 10.1155/2020/2368164.].

Efficacy and Safety of First-Line Immunotherapy in Combination with Chemotherapy for Patients with Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

BACKGROUND: The prognosis of patients with extensive-stage small cell lung cancer (SCLC) is poor. Adding an immune checkpoint inhibitor (ICI) to chemotherapy may exert a synergistic effect and improve survival outcomes. However, for treatment-naive extensive-stage SCLC patients, the efficacy of immunotherapy in combination with cytotoxic chemotherapy remains controversial. OBJECTIVE: To evaluate the benefits and risks of the combination of immunotherapy and chemotherapy and to assess the comparative effectiveness of different first-line treatment strategies for extensive-stage SCLC. METHODS: PubMed, Web of Science, EMBASE, and Cochrane Library were searched for randomized clinical trials studying different immunotherapeutics for patients with previously untreated extensive-stage SCLC up to Feb 16, 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS), and the secondary outcomes were objective response rate (ORR), disease control rate (DCR), and adverse events. RESULTS: We identified 141 published records, and 4 studies (comprising 2202 patients) were included in the analysis. Immunotherapy (including ipilimumab, atezolizumab, and durvalumab) plus chemotherapy was associated with better OS (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.75-0.93; risk ratio (RR) 0.90, 95% CI 0.81-1.00) and PFS (HR: 0.81, 95% CI 0.74-0.88; RR 0.96, 95% CI 0.93-0.99) than placebo plus chemotherapy. The addition of immunotherapy to chemotherapy showed similar improvement in ORR, DCR, and adverse events versus placebo plus chemotherapy. On the surface under the cumulative ranking (SUCRA) analysis, the anti-PD-L1 agent, atezolizumab, had the highest likelihood of achieving improved OS (93.4%) and PFS (95.0%). CONCLUSION: In the first-line setting, combining immunotherapy with chemotherapy is better than standard chemotherapy in terms of OS and PFS. Across the eligible studies, PD-L1 inhibitors might be preferred. Further explorations of more ICIs in the first-line treatment for extensive-stage SCLC patients should be needed.

The efficacy and safety of PD-1/PD-L1 inhibitors in patients with recurrent or metastatic nasopharyngeal carcinoma: A systematic review and meta-analysis.

OBJECTIVES: There is currently no effective salvage therapeutic modality that improves the survival outcomes of patients with recurrent or metastatic nasopharyngeal carcinoma. However, the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) inhibitors may provide clinical benefit for these advanced patients. MATERIALS AND METHODS: The databases, including PubMed, Web of Science, EMBASE and Cochrane Library, were systematically searched up to Nov 5, 2019. Data of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) rate, overall survival (OS) rate, and drug-related adverse events were extracted and pooled meta-analyzed. RESULTS: From 71 search records, eight studies were included in the systematic review, of which three were eligible for final meta-analysis. In recurrent or metastatic nasopharyngeal carcinoma patients treated with anti-PD-1 therapy, the pooled ORR was 27% (95% confidence interval [CI] 19-36%), DCR was 63% (95% CI 50-75%), 6 months PFS rate was 49% (95% CI 40-58%), 1-year PFS rate was 25% (95% CI 19-32%), 1-year OS rate was 61% (95% CI 49-72%). The pooled incidences of any grade and grade ≥ 3 drug-related adverse events were 94% and 20% respectively. CONCLUSION: We present the aggregate response rates, survival rates and incidences of drug-related adverse events for recurrent or metastatic nasopharyngeal carcinoma patients receiving PD-1/PD-L1 blockage treatment, which could provide useful information for future design of clinical studies. There is a need for more randomized controlled studies with head-to-head comparison of PD-1/PD-L1 inhibitors and traditional chemotherapeutic strategies to enable better recommendations for optimal advanced nasopharyngeal carcinoma treatment.

Downregulation of RIG-I mediated by ITGB3/c-SRC/STAT3 signaling confers resistance to interferon-α-induced apoptosis in tumor-repopulating cells of melanoma.

BACKGROUND: Interferon-α (IFN-α) plays a pivotal role in host antitumor immunity, and the evasion of IFN-α signaling pathway can lead to IFN-α resistance during the treatment of cancer. Although the interplay between IFN-α and tumor cells has been extensively investigated in differentiated tumor cells, much less attention has been directed to tumor-repopulating cells (TRCs). METHODS: Three-dimentional soft fibrin matrix was used to select and grow highly malignant and tumorigenic melanoma TRCs. The regulation of integrin ß3 (ITGB3)-c-SRC-STAT signaling pathway in melanoma TRCs was investigated both in vitro and in vivo. The relevant mRNA and protein expression levels were analyzed by qRT-PCR and western blot analysis. Immunoprecipitation and chromatin immunoprecipitation (ChIP) followed by qPCR (ChIP-qPCR) assays were performed to detect protein-protein and protein-DNA interactions. The clinical impacts of retinoic acid inducible gene-I (RIG-I) were assessed in melanoma datasets obtained from The Cancer Genome Atlas and Gene Expression Omnibus profiles. RESULTS: IFN-α-induced apoptosis was decreased in melanoma TRCs. Compared with conventional flask-cultured cells, IFN-α-mediated STAT1 activation was diminished in melanoma TRCs. Decreased expression of RIG-I in melanoma TRCs led to diminished activation of STAT1 via enhancing the interaction between Src homology region 2 domain-containing phosphatase-1 and STAT1. In addition, low expression levels of RIG-I correlated with poor prognosis in patients with melanoma. STAT3 was highly phosphorylated in TRCs and knockdown of STAT3 reversed the downregulation of RIG-I in TRCs. Knockdown of STAT3 resulted in STAT1 activation and increased expression of the pro-apoptosis genes in IFN-α-treated TRCs. Combined treatment of STAT3 inhibitor and IFN-α increased the apoptosis rate of TRCs. Disruption of ITGB3/c-SRC/STAT3 signaling pathway significantly elevated the efficiency of IFN-α-induced apoptosis of TRCs. CONCLUSIONS: In melanoma TRCs, ITGB3-c-SRC-STAT3 pathway caused RIG-I repression and then affect STAT1 activation to cause resistance to IFN-α-induced apoptosis. RIG-I is a prognostic marker in patients with melanoma. Combination of STAT3 inhibitor and IFN-α could enhance the efficacy of melanoma treatment. Our findings may provide a new concept of combinatorial treatment for future immunotherapy.

The effects and safety of PD-1/PD-L1 inhibitors on head and neck cancer: A systematic review and meta-analysis.

BACKGROUND: Inhibitors of programmed cell death-1 (PD-1) and its ligand (PD-L1) have been increasingly used in head and neck cancer therapy and reported to improve the outcomes with an acceptable safety profile. This systematic review and meta-analysis was conducted to assess the benefit and risk of PD-1/PD-L1 inhibitors in patients with head and neck cancer. METHOD: The PubMed, Cochrane Library, EMBASE and Web of Science databases were systematically searched to find potentially eligible studies up to May 30, 2019. Primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse events. RESULTS: Overall, this analysis consisted of nine eligible studies, with two randomized controlled trials and seven single arm trials. In the treatment of recurrent or metastatic head and neck cancer, PD-1 inhibitors showed significantly lower relative risk of death than standard-of-care therapy (odds ratio [OR] = 0.60, 95% confidence interval [CI]: 0.44-0.82, I2  = 0%, P = .001). Programmed cell death-1 inhibitors also decreased the risk of disease progression, however, there was no statistically significant difference of PFS between the treatments (OR = 0.69, 95% CI: 0.48-1.01, I2  = 0%, P = .05). Subgroup analysis showed that human papillomavirus (HPV) positive patients had higher response rates than HPV negative patients in PD-1/PD-L1 inhibitors-treated population (ORR: 18.8% vs 12.2%; DCR: 42.8% vs 34.4%). The most common any-grade and grade ≥3 treatment-related adverse events were fatigue (14.7%, 95% CI: 12.3%-17.1%) and aspartate aminotransferase increased (1.6%, 95% CI: 0.3%-2.9%), respectively. CONCLUSION: Programmed cell death-1 inhibitors prolonged OS in comparison with standard-of-care therapy in recurrent or metastatic head and neck cancer patients. Human papillomavirus positive patients were superior to HPV negative patients in the treatment of PD-1/PD-L1 inhibitors. More phase III randomized controlled trials are warranted to confirm our findings.

LINC01939 inhibits the metastasis of gastric cancer by acting as a molecular sponge of miR-17-5p to regulate EGR2 expression.

Accumulating evidence have suggested that long noncoding RNAs (lncRNAs) are known to regulate diverse tumorigenic processes. Recently, a novel lncRNA LINC01939 was underexpressed and emerged as a tumor suppressive lncRNA in gastric cancer (GC). In this study, we aimed to investigate the biological function and molecular mechanism of LINC01939 in GC. We found that LINC01939 expression was significantly downregulated in GC tissues and cell lines. Low expression of LINC01939 was correlated with tumor metastasis and shorter survival in GC patients. Functionally, LINC01939 overexpression remarkably inhibited the invasion and migration of GC cells in vitro and in vivo. Mechanistically, LINC01939 regulated the expression of early growth response 2 (EGR2) protein by competitively binding to miR-17-5p. Upregulation of miR-17-5p reversed GC metastasis and EMT process caused by LINC01939 by rescue analysis. Taken together, these results suggested that LINC01939 repressed GC invasion and migration by functioning as a ceRNA for miR-17-5p to regulate EGR2 expression. Our findings provided a novel prognostic marker and therapeutic target for GC patients.

Enhanced mitochondrial pyruvate transport elicits a robust ROS production to sensitize the antitumor efficacy of interferon-γ in colon cancer.

Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease.

Melatonin suppresses thyroid cancer growth and overcomes radioresistance via inhibition of p65 phosphorylation and induction of ROS.

Thyroid cancer is the most common endocrine carcinoma with increasing incidence worldwide and anaplastic subtypes are frequently associated with cancer related death. Radioresistance of thyroid cancer often leads to therapy failure and cancer-related death. In this study, we found that melatonin showed potent suppressive roles on NF-κB signaling via inhibition of p65 phosphorylation and generated redox stress in thyroid cancer including the anaplastic subtypes. Our data showed that melatonin significantly decreased cell viability, suppressed cell migration and induced apoptosis in thyroid cancer cell lines in vitro and impaired tumor growth in the subcutaneous mouse model in vivo. By contrast, irradiation of thyroid cancer cells resulted in elevated level of phosphorylated p65, which could be reversed by cotreatment with melatonin. Consequently, melatonin synergized with irradiation to induce cytotoxicity to thyroid cancer, especially in the undifferentiated subgroups. Taken together, our results suggest that melatonin may exert anti-tumor activities against thyroid carcinoma by inhibition of p65 phosphorylation and induction of reactive oxygen species. Radio-sensitization by melatonin may have clinical benefits in thyroid cancer.

HOXC6 predicts invasion and poor survival in hepatocellular carcinoma by driving epithelial-mesenchymal transition.

Aberrant expression of HOXC6 has been reported in several malignant tumors, yet little is known about the value of HOXC6 in invasion and prognosis of hepatocellular carcinoma (HCC). HOXC6 expression was positively correlated with high AFP level, liver cirrhosis, larger tumor, vascular invasion and BCLC stage. Kaplan-Meier analysis revealed that HOXC6 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, HOXC6 status could act as prognostic predictor in different risk subgroups. Moreover, HOXC6 maintained its prognostic value in different ability of invasiveness. Furthermore, combination of HOXC6 and serum AFP could be a potential predictor for survival in HCC patients. Additionally, further study showed that HOXC6 may promote invasion of HCC by driving epithelial-mesenchymal transition (EMT). Knockdown of HOXC6 significantly decreased the migration and invasion of HCC cells and changed the expression pattern of EMT markers. An opposite expression pattern of EMT markers was observed in HOXC6-transfected cells. In addition, immunohistochemistry and RT-PCR results further confirmed this correlation. In conclusion, HOXC6 contributes to invasion by inducing EMT pathway and predicts poor prognosis of HCC. HOXC6/AFP expression may help to distinguish the different risks of HCC patients after hepatectomy.

CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling.

Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4-transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.

Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages.

BACKGROUND: Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS: The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS: HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS: HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.

Influence of designer self-assembling nanofiber scaffolds containing anti-cancer peptide motif on hepatoma carcinoma cells.

Nanotechnology provides a novel scope for cancer therapeutics. Nanoscale platforms could influence the survival, adhesion, and migration of cancer cells through altering the tumor microenvironments. We report here the development of an anti-tumor material designed specifically for cancer therapy. We synthesized a 48-amino acid peptide RADA-KLA, which could self-assemble into nanostructures with antitumor activities. We tested the microstructure of RADA-KLA nanofiber scaffold using transmission electron microscopy (TEM) and accessed rheological properties of the material. Then, we demonstrated the effects of RADA-KLA nanofibers on hepatoma carcinoma cells. We found that RADA-KLA self-assembling peptide scaffold could induce cell death, and inhibit adhesion and migration of hepatoma carcinoma cells. Our results indicate that the designer peptide scaffold has anti-tumor activities and could be used for cancer therapy. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2329-2334, 2017.

Melittin-Containing Hybrid Peptide Hydrogels for Enhanced Photothermal Therapy of Glioblastoma.

The design of biocompatible and efficacious anticancer biomaterials to achieve relatively low tumor recurrence rates is the main pursuit of cancer photothermal therapy (PTT). RADA16-I is a synthetic amphiphilic peptide with the sequence RADARADARADARADA that can self-assemble into a peptide nanofiber hydrogel. In this study, we synthesized a novel melittin-RADA32-indocyanine green (ICG) hydrogel ("MRI hydrogel"), which contains melittin in the peptide hydrogel backbone and ICG in the hydrogel matrix, for enhanced PTT of glioblastomas. The MRI hydrogel exhibited physiologic characteristics similar to those of the RADA16 hydrogel, while displaying concentration-dependent cytotoxicity to C6 glioma cells and photothermal effects. The in vivo biodistribution of the MRI hydrogel was visualized by near-infrared fluorescence and photoacoustic imaging. More importantly, in vivo PTT provided by the MRI hydrogel significantly reduced the tumor size and the tumor recurrence rate compared with the RADR16-ICG hydrogel and other controls, suggesting a synergistic effect of MRI hydrogel-carried melittin and ICG-based PTT treatment. Thus, MRI provides an alternative tool for the safe and efficient PTT treatment of tumors.