Clinical Significance of Pim-1 in Human Cancers: A Meta-analysis of Association with Prognosis and Clinicopathological Characteristics.

BACKGROUND: Pim-1 is overexpressed in cancer tissues and plays a vital role in carcinogenesis. However, its clinical significance in cancers is not fully verified by meta-analysis, especially in relation to prognosis and clinicopathological features. METHODS: Four databases, PubMed, Embase, Cochrane Library, and Web of Science, were searched. Literature screening and data extraction according to the inclusion and exclusion criteria. The quality of the included literatures was evaluated using the Newcastle-Ottawa scale and the data analysis was performed using STATA and Review Manager software. RESULTS: 15 articles were finally included for meta-analysis, involving 1651 patients. Effect-size pooling analysis showed that high Pim-1 was related to poor overall survival (OS) (HR 1.68 [95% CI 1.17-2.40], P = .004) and disease-free survival (DFS) (HR 2.15 [95 %CI 1.15-4.01], P = .000). Subgroup analysis indicated that the detection techniques of Pim-1 were the main sources of heterogeneity, and 2 literatures using quantitative polymerase chain reaction (qPCR) for Pim-1mRNA had high homogeneity (I2 = .0%, P = .321) in OS. Another 13 studies that applied immunohistochemistry (IHC) for Pim-1 protein had significant heterogeneity (I2=82.2%, P = .000; I2=92%, P = .000) in OS and DFS, respectively, and further analysis demonstrated that ethnicity, sample size, and histopathological origin were considered to be the main factors affecting their heterogeneity. In addition, high Pim-1 was associated with lymph node metastasis (OR 1.40 [95% CI 1.02-1.92], P = .04), distant metastasis (OR 2.69 [95%CI 1.67-4.35], P < .0001), and clinical stage III-IV (OR .7 [95% CI .50-.96, P = .03). Sensitivity analysis suggested that the pooled results of each effect-size were stable and reliable, and there was no significant publication bias (P = .138) in all included articles. CONCLUSION: High Pim-1 can not only predict poor OS and DFS of cancer, but also help to infer the malignant clinical characteristics of tumor metastasis. Pim-1 may be a potential and promising biomarker for early diagnosis, prognostic analysis and targeted therapy of tumors.

Comment on: an orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent.

Recently we read a paper in Investigational New Drugs "An orally antitumor chalcone hybrid inhibited HepG2 cells growth and migration as the tubulin binding agent". Chalcone hybrid 9, a novel chalcone derivative, may be a promising agent for the treatment of hepatocellular carcinoma. However, there are some problems in this paper that are worthy of comment. Human hepatocellular carcinoma HepG2 cells from Shanghai Research Science Limited Company could generate xenograft in nude mice and chalcone hybrid 9 suppressed the growth of HepG2 tumor. However, according to the description of cell bank of Chinese Academy of Science and ATCC, HepG2 cells are no tumorigenic. Similarly, our lab also confirmed that HepG2 cells cannot demonstrate tumorigenic ability in nude mice. Therefore, this discrepancy raised our concern about HepG2 xenograft in the paper.

Nimotuzumab, an Anti-EGFR Monoclonal Antibody, in the Treatment of Nasopharyngeal Carcinoma.

Epidermal growth factor receptor (EGFR) is highly expressed in most of Nasopharyngeal carcinoma (NPC) samples and is associated with poor outcomes. Therefore, targeting EGFR may be a promising strategy to improve patient prognosis. Nimotuzumab is a humanized anti-EGFR monoclonal antibody. Recently, accumulating evidence has demonstrated that combination nimotuzumab and induction chemotherapy, radiotherapy, or concurrent chemoradiotherapy confer benefits for patients with NPC. Moreover, the side effects of such regimes are tolerable. In this review, we focus on the current data of nimotuzumab in clinical trials in the treatment of NPC.

A positive feedback loop between Wnt/ß-catenin signaling and hTERT regulates the cancer stem cell-like traits in radioresistant nasopharyngeal carcinoma cells.

Radioresistance may be induced by cancer stem cells (CSCs), while the biological traits of CSCs need to be retained by telomerase. The telomerase activity mainly depends on the transcriptional regulation of human telomerase reverse transcriptase (hTERT). Moreover, Wnt/ß-catenin signaling is also considered essential for maintaining the CSC phenotypes. In the previous study, we discovered that the radioresistant nasopharyngeal carcinoma cells CNE-2R displayed CSC-like traits, as well as high expression of hTERT and ß-catenin, but whether hTERT and ß-catenin were involved in regulating the CSC-like traits and radiosensitivity of CNE-2R cells remained unclear. In this study, our results suggested that hTERT could positively regulate the expression of CSC-related proteins, as well as the cytoplasm- and nucleus-ß-catenin, but it could not markedly regulate the expression of total ß-catenin in CNE-2R cells. Meanwhile, Wnt/ß-catenin signaling had a positive regulatory effect on the expression of hTERT and CSC-related proteins. Moreover, there was a ß-catenin/hTERT protein complex in CNE-2R cells, indicating that ß-catenin could directly interact with hTERT protein. Our results also revealed that silencing hTERT or suppressing Wnt/ß-catenin signaling could attenuate telomerase activity and radioresistance of CNE-2R cells; while suppressing Wnt/ß-catenin signaling, the telomerase activity and radioresistance could be reversed through overexpressing hTERT. Taken together, we have outlined a positive feedback loop between Wnt/ß-catenin signaling and hTERT in CNE-2R cells, which can regulate the telomerase activity and CSC-like traits, thus regulating the radiosensitivity. Therefore, blocking Wnt/ß-catenin signaling transduction and interfering with hTERT expression may be a promising approach for targeting radioresistant nasopharyngeal carcinoma cells with CSC-like traits.

Exosomes overexpressing miR-34c inhibit malignant behavior and reverse the radioresistance of nasopharyngeal carcinoma.

BACKGROUND: Malignant behavior and radioresistance, which severely limits the efficacy of radiation therapy (RT) in nasopharyngeal carcinoma (NPC), are associated with tumor progression and poor prognosis. Mesenchymal stem cells (MSCs) are used as a therapeutic tool in a variety of tumors. The aim of this study was to reveal the effect of tumor suppressor microRNA-34c-5p (miR-34c) on NPC development and radioresistance, as well as to confirm that exosomes derived from MSCs overexpressing miR-34c restore the sensitivity to radiotherapy in NPCs. METHODS: Potentially active microRNAs were screened by cell sequencing, Gene Expression Omnibus (GEO) database analysis, and analysis of clinical serum samples from 70 patients. The expression of genes and proteins was detected by Western blotting, quantitative reverse transcription PCR (qRT-PCR), and immunohistochemistry (IHC). Proliferation, apoptosis, invasion, migration and radioresistance of NPC were detected. Luciferase reporter assays were used to verify the interactions of microRNAs with their downstream targets. MSCs exosomes were isolated by ultrafiltration and verified by electron microscopy and nanoparticle tracking technology. RESULTS: The expression of miR-34c was associated with the occurrence and radiation resistance of NPC. In vitro and in vivo experiments indicated that overexpression of miR-34c inhibit malignant behavior such as invasion, migration, proliferation and epithelial-mesenchymal transition (EMT) in NPCs by targeting ß-Catenin. In addition, we found alleviated radioresistance upon miR-34c overexpression or ß-catenin knockdown in NPCs. Exosomes derived from miR-34c-transfected MSCs attenuated NPC invasion, migration, proliferation and EMT. Moreover, miR-34c-overexpressing exosomes drastically increased radiation-induced apoptosis in NPC cells. CONCLUSION: miR-34c is a tumor suppressor miR in NPC, which inhibits malignant behavior as well as radioresistance of tumor. Therefore, exogenous delivery of miR-34c to NPCs via MSC exosomes inhibits tumor progression and increases the efficiency of RT. Combination IR with miR-34c-overexpressing exosomes may be effective treatment for radioresistant NPCs.

Precision drugs for recurrent or metastatic nasopharyngeal carcinoma (Review).

Nasopharyngeal carcinoma (NPC) is a malignancy that is common in Southern China, South-East Asia and North Africa. Platinum-based chemotherapy is currently the main treatment option for the first-line therapy of recurrent and/or metastatic NPC (RM-NPC). However, the outcome of patients with advanced disease remains poor after treatment with standard chemotherapy, as patients eventually became resistant to chemotherapy. Other strategies, such as targeted therapy and immunotherapy, offer alternative options for patients due to their reported efficacy and manageable toxicities. This suggests that these modalities, either as monotherapy or in combination with chemotherapy, may serve as viable treatment options for RM-NPC. The present review provides a comprehensive summary of the clinical data of targeted therapy and immunotherapy for RM-NPC, with the aim of broadening the understanding of RM-NPC management.

Depicting the Implication of miR-378a in Cancers.

MicroRNA-378a (miR-378a), including miR-378a-3p and miR-378a-5p, are encoded in PPARGC1B gene. miR-378a is essential for tumorigenesis and is an independent prognostic biomarker for various malignant tumors. Aberrant expression of miR-378a affects several physiological and pathological processes, including proliferation, apoptosis, tumorigenesis, cancer invasion, metastasis, and therapeutic resistance. Interestingly, miR-378a has a dual functional role in either promoting or inhibiting tumorigenesis, independent of the cancer type. In this review, we comprehensively summarized the role and regulatory mechanisms of miR-378a in cancer development, hoping to provide a direction for its potential use in cancer therapy.

UC2288 induces cell apoptosis of nasopharyngeal carcinoma cells via inhibiting EGFR/ERK pathway.

Radiotherapy and chemotherapy are the standard care for patients with nasopharyngeal carcinoma (NPC). These treatments cause some severe toxicity and about 30% of patients develop recurrence and metastases after treatment. UC2288 is structurally similar to sorafenib, a multikinase inhibitor. However, studies about the effects of UC2288 on tumors are few. Here, UC2288 inhibited proliferation and induced apoptosis of NPC cells in a dose- and time-dependent manner. Using western blot and immunofluorescence assay, we found that UC2288 promoted DNA damage. In addition, UC2288 decreased the phosphorylation of EGFR and ERK. Moreover, pretreatment with EGF partially rescued cell viability suppressed by UC2288. In conclusion, UC2288 suppressed the growth of NPC via inhibiting EGFR/ERK pathway and it may be a promising therapeutic option for NPC.

Prognostic Role of EGFR/p-EGFR in Patients With Nasopharyngeal Carcinoma: A Meta-Analysis.

BACKGROUND: The prognostic value of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) expression in nasopharyngeal carcinoma remains controversial. A meta-analysis was performed to investigate prognostic significance of EGFR/p-EGFR expression in patients with nasopharyngeal carcinoma. METHODS: Literatures published before November 2020 were systematically searched in relevant databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan fang databases. STATA 13 statistical software was used to analyze the pooled hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity of the studies was examined by I2. Sensitivity and subgroup analysis were performed to explore sources of heterogeneity. The potential publication bias was assessed using both Egger's and Begg's tests. RESULTS: A total of 20 literatures with 1545 patients were included for the meta-analysis. The meta-analysis results suggested that high expression of EGFR was significantly associated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.24-3.15, P = 0.001) and disease-free survival (DFS) (HR = 2.58, 95% CI: 1.87-3.56, P = 0.000). However, it was not significantly associated with progression-free survival (PFS) (HR = 1.85, 95% CI: 0.90-3.82, P = 0.09) and distant metastasis-free survival (DMFS) (HR = 1.39, 95% CI: 0.73-2.67, P = 0.319). The subgroup analysis indicated that patients with EGFR high expression in studies of higher TNM stage (III-IV) ratio had significantly poor OS (HR = 2.27, 95% CI: 1.09-4.73, P = 0.03), but heterogeneity existed in studies (I2 = 95.1%, P = 0.000). Sensitivity analyses revealed that EGFR expression did not significantly affect OS by an individual study solely, indicating there was inherent heterogeneity in OS cohorts. There was no significant heterogeneity among eight studies in the DFS cohorts (I2 = 0%, P = 0.606). There was significant heterogeneity between EGFR expression and DMFS (I2 = 82.8%, P = 0.000). Sub-group analysis in differentiated carcinoma demonstrated a smaller heterogeneity (I2 = 33.2%). In addition, p-EGFR high expression had no significant correlation with OS (HR = 1.00, 95% CI: 0.88-1.14, P = 0.982) and DMFS (HR = 1.21, 95% CI: 0.96-1.52, P = 0.112). The heterogeneity among p-EGFR and OS studies was small (I2 = 21%, P = 0.26). There was no significant heterogeneity in the DMFS cohorts (I2 = 0%, P = 0.497). CONCLUSION: EGFR high-expression was significantly associated with poor OS and DFS, which may serve as a prognostic predictor for nasopharyngeal cancer. SYSTEMATIC REVIEW REGISTRATION: [https://www.crd.york.ac.uk/PROSPERO], identifier [number CRD42021258457].

CD166 promotes cancer stem cell-like phenotype via the EGFR/ERK1/2 pathway in the nasopharyngeal carcinoma cell line CNE-2R.

AIMS: The present study aimed to investigate the role and underlying mechanisms of CD166 in cancer stem cell-like (CSCs) phenotype of the radioresistant nasopharyngeal carcinoma cell CNE-2R. MAIN METHODS: Established CD166-shRNA- CNE-2R cell line by lentivirus-mediated silencing CD166. Then, CSC-related genes mRNAs and proteins, and EGFR/ERK1/2 signaling pathway were detected using RT-PCR and western blot. Sphere formation assay was performed to evaluate the sphere formation capacity in CD166-shRNA- CNE-2R cells. The tumorigenesis ability in vivo was examined in nude mice mode. KEY FINDINGS: Downregulation of CD166 inhibited the expression of the CSC-related genes, pEGFR and pERK in vitro and vivo. The capacity to form spheres and tumorigenesis was significantly decreased in CD166-shRNA cells. Furthermore, EGF-stimulated CD166-shRNA cells exhibited an increase in CSC-like traits by activating EGFR/ERK1/2 signaling. SIGNIFICANCE: CD166 induced CSCs formation by activating the EGFR/ERK1/2 signaling pathway in nasopharyngeal carcinoma, which may serve as a critical molecular target for NPC therapeutic strategies.

Deciphering the Roles of IFITM1 in Tumors.

Interferon (IFN)-induced transmembrane protein 1 (IFITM1), a member of the IFN-induced transmembrane protein family, is reported to be highly expressed in tumor tissues as well as cancer cell lines, and it is an independent prognostic biomarker for patients with certain tumor types, such as gallbladder carcinoma, esophageal adenocarcinoma, colorectal cancer, and gastric cancer. Moreover, overexpression of IFITM1 promotes tumor cell proliferation, invasion, metastasis, angiogenesis, and therapeutic resistance, including endocrine therapy, chemotherapy, and radiotherapy resistance. Due to these diverse functions of IFITM1 in tumors, targeting IFITM1 may provide a novel strategy for cancer treatment and be highly desirable to improve cancer patient outcomes. Herein, we decipher the role of IFITM1 in cancer in detail.

Anti-EGFR therapies in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a common malignant tumor in Southern China and South-East Asia. Regardless of initiative high response to radiotherapy, parts of patients still have relapses and metastases. It is reported that epidermal growth factor receptor (EGFR) is highly expressed in most of NPC and is a poor prognostic factor. Targeting EGFR therapies including monoclonal antibodies and EGFR tyrosine kinase inhibitors (EGFR-TKIs), offer different benefits and toxicities for patients with NPC. Herein, we summarize the clinical evidence of anti-EGFR therapies in the management of NPC and provide a direction for the treatment and research of NPC in the future.

STAT3 signaling in ovarian cancer: a potential therapeutic target.

Accumulating evidence has shown that Signal Transducer and Activator of Transcription 3 (STAT3) is thought to be a promising target for cancer therapy as STAT3 is frequently overexpressed in a wide range of cancer cells as well as clinical specimens, promoting tumor progression. It is widely accepted that STAT3 regulates a variety of cellular processes, such as tumor cell growth, survival, invasion, cancer stem cell-like characteristic, angiogenesis and drug-resistance. In this review, we focus on the role of STAT3 in tumorigenesis in ovarian cancer and discuss the existing inhibitors of STAT3 signaling that can be promisingly developed as the strategies for ovarian cancer therapy.

VEGF promotes migration and invasion by regulating EMT and MMPs in nasopharyngeal carcinoma.

Background: Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. Accumulating data have indicated that VEGF is involved in tumour metastasis. However, the mechanism through which VEGF regulates nasopharyngeal carcinoma (NPC) metastasis is largely unknown. This study aimed to examine the biological function of VEGF in NPC metastasis and its underlying mechanism. Methods: We used western blotting and qPCR to examine the difference in VEGF expression between NPC cells and the immortalized nasopharyngeal epithelial cell line NP69. Wound healing assays, transwell assays and animal experiments were used to further verify the role of VEGF in the invasion and migration of NPC cells. The protein levels of the epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) family were analysed by immunofluorescence (IF) and western blotting. Enzyme-linked immunosorbent assay (ELISA) and transwell assays were used to determine whether VEGF enhanced the invasion and migration of NPC cells in an autocrine manner. Western blotting was used to examine how autocrine VEGF-VEGFR2 signalling regulated EMT and MMPs. Results: We observed higher levels of VEGF in NPC cells than that in NP69 cells and identified an association between high VEGF levels and tumour invasion and migration. Mechanistically, the VEGF-mediated increase in EMT markers, MMP2 and MMP9 promoted NPC cell invasion and migration. Additionally, NPC cells secreted VEGF to promote cell invasion, migration and angiogenesis. Autocrine VEGF-VEGFR2 signalling increased ERK1/2 phosphorylation, promoted EMT process and MMPs at the indicated times. Conclusion: This study revealed that VEGF plays a role in controlling NPC cell metastasis by regulating EMT markers and MMPs in an autocrine manner.

VEGF knockdown enhances radiosensitivity of nasopharyngeal carcinoma by inhibiting autophagy through the activation of mTOR pathway.

Vascular endothelial growth factor (VEGF) is an important pro-angiogenic factor. VEGF was reported to promote the occurrence of autophagy, which enhanced the radioresistance of tumors. The purpose of this study was to investigate the influence of VEGF silencing on the radiosensitivity of nasopharyngeal carcinoma (NPC) cells and the underlying mechanisms. The radiosensitivity of NPC cells after VEGF silencing was detected by cell counting kit 8 (CCK-8) and clonogenic assay, while cell cycle and apoptosis were detected by flow cytometry. The processes of DNA damage, repair and autophagy were examined by immunofluorescence and western blotting. The interaction between VEGF and mTOR was confirmed by western blotting and co-immunoprecipitation studies. The effect of VEGF on radiosensitivity of NPC cells was investigated in vivo using a xenograft model. Furthermore, immunohistochemistry and TUNEL assays were used to verify the relationship between autophagy and radiosensitivity in NPC after VEGF depletion. Downregulation of VEGF significantly inhibited cell proliferation and induced apoptosis of NPC cells after radiotherapy in vitro and in vivo. In addition, VEGF knockdown not only decreased autophagy level, but also delayed the DNA damage repair in NPC cells after irradiation. Mechanistically, silencing VEGF suppressed autophagy through activation of the mTOR pathway. VEGF depletion increased radiosensitivity of NPC cells by suppressing autophagy via activation of the mTOR pathway.

The Double-Edge Role of the Addition of Adjuvant Chemotherapy to Concurrent Chemoradiotherapy in the Treatment of Nasopharyngeal Carcinoma.

PURPOSE: To construct a prognostic index (PI) for overall survival (OS) to stratify nasopharyngeal carcinoma (NPC) into high-risk and low-risk groups. We also applied the model to investigate the role of the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) regimens for the treatment of NPC. METHODS: A prognostic model was established based on a retrospective study of 362 patients from January 2008 to June 2011. The discriminative and calibration abilities of the model were evaluated by Harrell's concordance index (C-index), and calibration curves. Bootstrapping was used to perform for internal validation. External validation was conducted using 324 patients diagnosed with NPC from July 2011 to December 2012 at the same institution. Survival analyses were performed between CCRT-AC and CCRT alone groups for the high-risk and low-risk groups. RESULTS: The primary PI comprised covariates that were associated with OS in the training cohort, including T stage, N stage, age, and plasma alkaline phosphatase (ALP). Internal and external validation showed that the discrimination of the PI for OS was significantly better than that of the 8th edition AJCC staging system. Discretization by using a fixed PI score cut-off of 407.96 determined from the training data set yielded high- and low-risk subgroups with distinct OS outcomes in the validation cohort. Adjuvant chemotherapy improved OS in high-risk patients (HR 0.620, 95% CI 0.408 to 0.941; P = 0.023) but increased the risk of distant metastasis (HR, 4.222, 95% CI, 0.959 to 18.585; P = 0.038) in low-risk patients. CONCLUSION: The proposed prognostic model achieved good prediction and calibration of OS for patients with NPC. The addition of adjuvant chemotherapy might be a double-edged sword, bringing survival benefit to high-risk patients but greater risk of distant metastasis to low-risk patients.