FAP positive cancer-associated fibroblasts promote tumor progression and radioresistance in esophageal squamous cell carcinoma by transferring exosomal lncRNA AFAP1-AS1.

Cancer-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in the tumor microenvironment, which play important roles in regulating tumor progression and therapy resistance by transferring exosomes to cancer cells. However, how CAFs modulate esophageal squamous cell carcinoma (ESCC) progression and radioresistance remains incompletely understood. The expression of fibroblast activation protein (FAP) in CAFs was evaluated by immunohistochemistry in 174 ESCC patients who underwent surgery and 78 pretreatment biopsy specimens of ESCC patients who underwent definitive chemoradiotherapy. We sorted CAFs according to FAP expression, and the conditioned medium (CM) was collected to culture ESCC cells. The expression levels of several lncRNAs that were considered to regulate ESCC progression and/or radioresistance were measured in exosomes derived from FAP+ CAFs and FAP- CAFs. Subsequently, cell counting kit-8, 5-ethynyl-2'-deoxyuridine, transwell, colony formation, and xenograft assays were performed to investigate the functional differences between FAP+ CAFs and FAP- CAFs. Finally, a series of in vitro and in vivo assays were used to evaluate the effect of AFAP1-AS1 on radiosensitivity of ESCC cells. FAP expression in stromal CAFs was positively correlated with nerve invasion, vascular invasion, depth of invasion, lymph node metastasis, lack of clinical complete response and poor survival. Culture of ESCC cells with CM/FAP+ CAFs significantly increased cancer proliferation, migration, invasion and radioresistance, compared with culture with CM/FAP- CAFs. Importantly, FAP+ CAFs exert their roles by directly transferring the functional lncRNA AFAP1-AS1 to ESCC cells via exosomes. Functional studies showed that AFAP1-AS1 promoted radioresistance by enhancing DNA damage repair in ESCC cells. Clinically, high levels of plasma AFAP1-AS1 correlated with poor responses to dCRT in ESCC patients. Our findings demonstrated that FAP+ CAFs promoted radioresistance in ESCC cells through transferring exosomal lncRNA AFAP1-AS1; and may be a potential therapeutic target for ESCC treatment.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified. METHODS: Firstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo. RESULTS: Our study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression. CONCLUSION: circFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.

DNA methylation data-based prognosis-subtype distinctions in patients with esophageal carcinoma by bioinformatic studies.

Esophageal carcinoma (ESCA) is caused by the accumulation of genetic and epigenetic alterations in esophageal mucosa. Of note, the earliest and the most frequent molecular behavior in the complicated pathogenesis of ESCA is DNA methylation. In the present study, we downloaded data of 178 samples from The Cancer Genome Atlas (TCGA) database to explore specific DNA methylation sites that affect prognosis in ESCA patients. Consequently, we identified 1,098 CpGs that were significantly associated with patient prognosis. Hence, these CpGs were used for consensus clustering of the 178 samples into seven clusters. Specifically, the samples in each group were different in terms of age, gender, tumor stage, histological type, metastatic status, and patient prognosis. We further analyzed 1,224 genes in the corresponding promoter regions of the 1,098 methylation sites, and enriched these genes in biological pathways with close correlation to cellular metabolism, enzymatic synthesis, and mitochondrial autophagy. In addition, nine representative specific methylation sites were screened using the weighted gene coexpression network analysis. Finally, a prognostic prediction model for ESCA patients was built in both training and validation cohorts. In summary, our study revealed that classification based on specific DNA methylation sites could reflect ESCA heterogeneity and contribute to the improvement of individualized treatment and precise prognostic prediction.

Clinical practice and outcome of radiotherapy for advanced esophageal squamous cell carcinoma between 2002 and 2018 in China: the multi-center 3JECROG Survey.

PURPOSE: To determine the survival and prognostic factors of esophageal squamous cell carcinoma (ESCC) patients undergoing radical (chemo)radiotherapy in the era of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) in China. MATERIAL AND METHODS: The Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG) conducted the first nationwide survey of nine institutions. Detailed information was accumulated on 5185 patients with ESCC who received definitive 3DCRT/IMRT between 2002 and 2018. Relevant prognostic factors were evaluated to assess their influence on overall and progression-free survivals. RESULTS: After a median follow-up time of 47.0 (0.9-157.4) months, the 1-year, 2-year, 3-year and 5-year overall survival rates of the whole group were 69.8%, 46.6%, 37.9% and 30.1%. The 1-year, 2-year, 3-year, and 5-year progression-free survival rates were 54.1%, 36.6%, 30.5% and 24.9%. Multivariate analysis demonstrated that sex, clinical stage, treatment modality and radiation dose were prognostic factors for OS. The survival of patients who received concurrent chemoradiotherapy (CCRT) was better than that of patients who received radiotherapy alone or sequential chemoradiotherapy. Patients receiving adjuvant chemotherapy after CCRT had a better OS than patients receiving CCRT alone. Patients receiving higher radiation dose had a better OS than those patients receiving low-dose radiotherapy. CONCLUSIONS: The survival of ESCC patients undergoing radical (chemo)radiotherapy was relatively satisfactory in the era of 3DCRTand IMRT. As the largest-scale multicenter research on esophageal cancer radiotherapy conducted in China, this study establishes national benchmarks and helps to provide references for subsequent related researches.

[Acceptance Test of Physical Properties of Perfexion Gamma Knife].

Objective The acceptance test of the physical performance for the newly installed PFX Gamma knife was carried out to provide a reference for the quality assurance of the equipment. Method According to the manufacturer's acceptance manual and Chinese health industry standards, the dose rate of the PFX Gamma knife with maximum collimators in the calibration center point, the focal spot dose distribution with all three collimator sizes, the distance between the RFP and the PPS calibration center point, and the multi-target position accuracy were measured by means of the acceptance tools. Results The average absorbed dose rate, as measured in April 29, 2019, was 3.295 Gy/min in the calibration center point by the maximum collimators, which was better than acceptance standard of 2.5 Gy/min. The focal spot dosimetry data measured by the film were basically the same as the TMR-10 data stored in the LGP. The difference in FWHM was 0.18±0.13 mm, and the difference in penumbra was 0.15±0.25 mm, which was normal and as expected. The distance between the RFP and PPS calibration center point in the three-dimensional space was 0.24 mm, which was better than the recommended value of the factory standard and the national standard. The maximum position deviation of multiple targets was 0.16 mm, which was also better than the factory standard of 0.5 mm. Conclusion The various physical performance indicators of the PFX Gamma knife met the acceptance standards of manufacturers and industries.

Does chemoradiotherapy benefit elderly patients with esophageal squamous cell cancer? A propensity-score matched analysis on multicenter data (3JECROG R-03A).

BACKGROUND: The aim of the present study was to assess the efficacy of concurrent chemoradiotherapy (CRT) or radiotherapy alone (RT-alone) in elderly patients with esophageal squamous cell carcinoma (ESCC). METHODS: The clinical data of patients with ESCC treated with RT-alone or CRT were collected and retrospectively reviewed. The 1-, 3- and 5-year overall survival (OS) rates and the clinical characteristics correlated with survival were analyzed statistically. Propensity score matching (PSM) analyses were used to compensate for differences in baseline characteristics between the CRT and RT-alone groups to confirm the survival difference. RESULTS: A total of 729 patients fulfilling the inclusion criteria were reviewed. Diabetes, primary tumor volume (pTV), primary tumor location (pTLo), clinical T stage,(cT) clinical N stage (cN), clinical M stage (cM) and short-term response to RT were independent factors influencing OS (P = 0.002-0.044). The 5-year OS rate was 26.6, 26.0 and 30.1% in the whole cohort, RT-alone and CRT groups, respectively. The survival difference between RT alone and CRT was not significant before or following PSM. Compared with the corresponding subgroups treated with RT alone, CRT significantly benefited patients with diabetes (P = 0.003), cT4 (P = 0.030) and cN0 (P = 0.049), whereas no benefit was identified between CRT and RT alone in the other subgroups, including cT1-3, cN1, cM, pTLo, pTV, age and gender. CONCLUSIONS: CRT with the current chemotherapy regimens may not improve the survival of elderly ESCC patients compared to RT-alone, except in patients with cT4 stage, cN0 stage or diabetes. However, due to the limitation of the retrospective nature of the current study, further clinical trials are required for confirmation.

Raltitrexed increases radiation sensitivity of esophageal squamous carcinoma cells.

BACKGROUND: Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been developed to increase the radiosensitivity of esophageal cancer, with some success. METHODS: This study was conducted to determine whether raltitrexed can enhance radiosensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines 24 h were incubated with raltitrexed or DMSO with or without subsequent irradiation. Cell Counting Kit assay-8 assay and clonogenic survival assay were used to measure the cell proliferation and radiosensitization, respectively. Flow cytometry was utilized to examine cell apoptosis and cell cycle distribution in different groups. Immunofluorescence analysis was performed to detect deoxyribonucleic acid (DNA) double-strand breaks. In addition, the expression levels of proteins that are involved in radiation induced signal transduction including Bax, Cyclin B1, Cdc2/pCdc2, and Cdc25C/pCdc25C were examined by western blot analysis. RESULTS: The results indicated that raltitrexed enhanced radiosensitivity of ESCC cells with increased DNA double-strand breaks, the G2/M arrest, and the apoptosis of ESCC cells induced by radiation. The sensitization enhancement ratio of 1.23-2.10 was detected for ESCC cells with raltitrexed treatment in TE-13 cell line. In vitro, raltitrexed also increased the therapeutic effect of radiation in nude mice. CONCLUSION: Raltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.

A multicenter phase III study comparing Simultaneous Integrated Boost (SIB) radiotherapy concurrent and consolidated with S-1 versus SIB alone in elderly patients with esophageal and esophagogastric cancer - the 3JECROG P-01 study protocol.

BACKGROUND: The importance of definitive radiotherapy for elderly patients with esophageal and esophagogastric-junction cancer is pronounced. However, little is known in terms of the best way to combine radiotherapy with other treatment options. This study aims to compare the efficiency of SIB radiotherapy alone with SIB radiotherapy concurrent and consolidated with S-1 for elderly patients. Comprehensive geriatric assessment is also incorporated in the procedure of treatment. METHODS/DESIGN: The study is a two arm, open, randomized multicenter Phase III trial with patients over 70 years old with stage IIA-IVB (UICC 2002, IVB only with metastasis to supraclavicular or celiac lymph nodes) squamous cell carcinoma or adenocarcinoma of esophagus or gastroesophageal junction. A total of 300 patients will be randomized using a 1:1 allocation ratio stratified by disease stage and study site. Patients allocated to the SIB arm will receive definitive SIB radiotherapy (95%PTV/PGTV 50.4Gy/59.92Gy/28f) while those randomized to SIB + S-1 arm will receive definitive SIB radiotherapy concurrent and consolidated with S-1. The primary endpoint of the trial is 1-year overall survival. Secondary objectives include progression-free survival, recurrence-free survival (local-regional and distant), disease failure pattern, toxicity profile as well as quality of life. Besides, detailed radiotherapy protocol and quality assurance procedure have been incorporated into this trial. DISCUSSION: The proportion of elderly patients in esophageal cancer is now growing, but there is a lack of evidence in term of treatment standard for this group of patients, which is what we aim to obtain through this prospective phase III study. TRIAL REGISTRATION: clinicaltrials.gov NCT02979691 . Registered November 22, 2016.

Correction to: A multicenter phase III study comparing Simultaneous Integrated Boost (SIB) radiotherapy concurrent and consolidated with S-1 versus SIB alone in elderly patients with esophageal and esophagogastric cancer - the 3JECROG P-01 study protocol.

Following publication of the original article [1], the authors reported that an error in the Methods/Design, Study design and objectives section (third sentence).

High-mobility group box 1 protein modulated proliferation and radioresistance in esophageal squamous cell carcinoma.

BACKGROUND AND AIM: The high-mobility group box 1 (HMGB1) protein plays an important role in a lot of biological behaviors, including DNA damage repair, gene transcription, cell replication, and cell death, and its expression is higher in many solid tumors tissues than in their adjacent normal tissues, and it is always involved in tumor proliferation, metastasis, therapeutic tolerance, and poor prognosis. However, HMGB1 in proliferation and radioresistance of esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, the effect of HMGB1 on proliferation, cell death, DNA damage repair and radioresistance, and its underlying mechanism was investigated in human ESCC. METHODS: The immunohistochemistry scores of tumor and adjacent normal tissues in ESCC tissue microarray were analyzed. Stable HMGB1 knockdown cell lines were constructed using Kyse150 and Kyse450 cells. Cell viability, radioresistance, apoptosis, autophagy, and DNA damage were determined using CCK-8, 5-ethynyl-2'-deoxyuridine, clonogenic survival assay, immunofluorescence, flow cytometry, and western blot assays. RESULTS: Differential analyses showed that the expression of HMGB1 in esophageal cancer tissue was significantly higher than that in adjacent normal tissues. The downregulation of HMGB1 could effectively inhibit proliferation, increase radiosensitivity, impair DNA damage repair abilities, reduce autophagy, and increase apoptosis rates in ESCC cells after irradiation. CONCLUSIONS: HMGB1 is expected to be a potential target for ESCC therapy and radiosensitization.

Fixed-jaw technique to improve IMRT plan quality for the treatment of cervical and upper thoracic esophageal cancer.

The purpose of this study was to investigate the potential advantages of the fixed-jaw technique (FJT) over the conventional split-field technique (SFT) for cervical and upper thoracic esophageal cancer (EC) patients treated with intensity-modulated radiotherapy. The SFT and FJT plans were generated for 15 patients with cervical and upper thoracic EC. Dosimetric parameters and delivery efficiency were compared. An area ratio (AR) of the jaw opening to multileaf collimator (MLC) aperture weighted by the number of monitor units (MUs) was defined to evaluate the impact of the transmission through the MLC on the dose gradient outside the PTV50.4, and the correlation between the gradient index (GI) and AR was analyzed. The FJT plans achieved a better GI and AR (P < 0.001). There was a positive correlation between the GI and AR in the FJT (r = 0.883, P < 0.001) and SFT plans (r = 0.836, P < 0.001), respectively. Moreover, the mean dose (Dmean ), V5Gy -V40Gy for the lungs and the Dmean , V5Gy -V50Gy for the body-PTV50.4 in the FJT plans were lower than those in the SFT plans (P < 0.05). The FJT plans demonstrated a reduction trend in the doses to the spinal cord PRV and heart, but only the difference in the heart Dmean reached statistical significance (P < 0.05). The FJT plans reduced the number of MUs and subfields by 5.5% and 17.9% and slightly shortened the delivery time by 0.23 min (P < 0.05). The gamma-index passing rates were above 95% for both plans. The FJT combined with target splitting can provide superior organs at risk sparing and similar target coverage without compromising delivery efficiency and should be a preferred intensity-modulated radiotherapy planning method for cervical and upper thoracic EC patients.

Silencing human epidermal growth factor receptor-3 radiosensitizes human luminal A breast cancer cells.

Endocrine therapy and radiotherapy are the main treatments for luminal A breast cancer. However, drug and radiotherapy resistance could occur during long-term treatment, leading to local recurrence and distant metastasis. Some studies have found that drug resistance might be related to human epidermal growth factor receptor-3 (HER3) overexpression. However, whether HER3 plays a role in radiotherapy resistance is unknown. The purpose of this study is to elucidate the effect of HER3 in radiotherapy and to assess whether HER3 could be a potential target for radiosensitivity. We used retroviruses to construct stable low expression of HER3 in MCF-7 and ZR75-1cells. The CCK-8 assay was used to observe proliferation. Colony-forming assay was used to detect radiosensitivity. Flow cytometry was used to observe the cell cycle and apoptosis. Immunofluorescence assay was used to detect the number of γH2AX foci in the nucleus with or without ionizing radiation (IR). Western blot analysis was used to verify the change of relative proteins. Nude mice were used to observe tumor growth in vivo. In our study, silencing HER3 reduced cell proliferation and clone formation ability after IR, so silencing HER3 increased the sensitivity of luminal A breast cancer cells to radiotherapy. In terms of radiosensitivity mechanisms, it is suggested that the silencing of HER3 enhanced IR-induced DNA damage, reduced DNA repair, and increased apoptosis and G2 /M arrest. In addition, silencing HER3 combined with IR clearly inhibited the transplanted tumor growth in vivo. Therefore, we concluded that HER3 played a role in radiotherapy resistance. Silencing HER3 increased the radiosensitivity of luminal A breast cancer cells and HER3 could be a potential target for radiosensitivity.

Endostatin combined with radiotherapy suppresses vasculogenic mimicry formation through inhibition of epithelial-mesenchymal transition in esophageal cancer.

The growth of solid tumors requires angiogenesis to provide oxygen and nutrients and to support cell proliferation. The switch from an avascular to a vascular phenotype is typically related to acceleration of tumor growth. Anti-angiogenic therapy is becoming a very promising way for malignant tumors. Meanwhile, malignant tumor cells themselves were able to develop the formation of cell-lined vessels that contribute to tumor neovascularization and supply the nutrients and oxygen, which is called vasculogenic mimicry (VM). However, the molecular mechanism of VM remains unclear. The purpose of this study was to investigate the efficacy of the novel recombinant human endostatin (rh-Endo) protein combined with radiotherapy on human esophageal squamous cell carcinoma (ESCC) cell lines Eca-109 and TE13. Our results showed that rh-Endo combined with radiotherapy significantly inhibited the proliferation, migration, invasion, and VM of human esophageal cancer cells in a dose-dependent manner; however, it has no direct effect on apoptosis of carcinoma cells, which indicated that rh-Endo combined with radiotherapy significantly changed the microenvironment of esophageal carcinoma, and played an important role in preventing distant metastasis. Our findings suggested that rh-Endo inhibited the metastasis of esophageal cancer and the activation of AKT pathway, and the down-regulation of epithelial-mesenchymal transition (EMT) may be associated with such effect of rh-Endo. These results also supported the bright prospect of rh-Endo combined with radiotherapy for clinical applications in the future.

Gambogic acid enhances the radiosensitivity of human esophageal cancer cells by inducing reactive oxygen species via targeting Akt/mTOR pathway.

Radiotherapy is a widespread treatment in human solid tumors. However, therapy resistance and poor prognosis are still problems. Gambogic acid (GA), extracted from the dried yellow resin of gamboges, has an anticancer effect against various types of cancer cells. To explore the radiosensitivity of GA on esophageal cancer cell line TE13, cell viability was tested by Cell Counting Kit-8 (CCK-8) assay, colony formation assay was used to assess the effects of GA on the radiosensitivity of TE13, and flow cytometry was performed to meter the percentage of apoptosis. The protein levels of microtubule-associated protein 1 light chain 3 (LC3), caspase3, caspase8, casepase9, pAkt, and p-mammalian target of rapamycin (p-mTOR) were tested using Western blot. The distribution of LC3 was detected by immunofluorescence. Additionally, we also examined reactive oxygen species (ROS) expression by laser scanning confocal microscope (LSCM). The cells were transfected with adenovial vector to monitor the autophagy through the expression of green fluorescent protein (GFP-red fluroscent protein (RFP)-LC3. The rates of apoptotic cells in combined-treated TE13 increased significantly compared with the control groups in accordance with the results of Western blot. The clonogenic survival assay showed that GA enhances radiosensitivity with a sensitizing enhancement ratio (SER) of 1.217 and 1.436 at different concentrations. The LC3-II protein level increased in the combined group indicating the increase of autophagy incidence, and the results of GFP-RFP-LC3 experiment showed that GA may block the process of autophagic flux in TE13 cells. Moreover, we successfully demonstrated that ROS is involved in the induction of autophagy. ROS-mediated autophagy depends on the inhibition of the Akt/mTOR pathway. Taken together, GA induced radiosensitivity involves autophagy and apoptosis which are regulated by ROS hypergeneration and Akt/mTOR inhibition.

Autophagy and its function in radiosensitivity.

Autophagy differs from apoptosis and is independent of phagocytes by the appearance of autophagosomes, autolysosomes, and complete nuclei in the cell. This process significantly contributes to the antineoplastic effects of radiation. Radiation is an important strategy in cancer treatment; however, many types of cancer show radioresistance. The effects of radiotherapy are affected by factors, including the degree of tumor tissue hypoxia, the ability to repair DNA damage, and the presence of cancer stem cells. We review the relationships among autophagy, the three factors in cancer radiation, and the possible underlying molecular mechanisms. The therapeutic implications of these relationships and mechanisms in clinical settings are also discussed.

Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways for gastric adenocarcinoma.

To demonstrate candidate single nucleotide polymorphisms that might affect susceptibility to gastric adenocarcinoma as well as their potential mechanisms and pathway hypotheses, we performed a genome-wide association study dataset of gastric adenocarcinoma. Our study included 472,342 single nucleotide polymorphisms from 2766 cases of gastric cardia adenocarcinoma cases and 11,013 subjects from north central China as control groups. The identify candidate causal SNPs and pathways (ICSNPathway) analysis was employed to identify 13 candidate single nucleotide polymorphisms, nine genes, and 15 pathways. The top three candidate SNPs were rs3765524 (-log10(p) = 8.556), rs2274223 (-log10(p) = 8.633), and rs2076472 (-log10(p) = 3.205). The strongest mechanism involved the modulation of rs4745 and rs12904, thereby affecting their regulatory roles in ephrin receptor binding (p = 0.001; FDR = 0.005). The second strongest hypothetical biological mechanism was that rs932972 and rs1052177 alters the regulatory role of the glycolysis pathway (p < 0.001; FDR = 0.013). The most significant pathway was the regulation of the ephrin receptor binding pathway, which involved EFNA1, TIAM1, EFNA5, EFNB2, and EFNB3.

STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma.

The radioresistance of esophageal squamous cell carcinoma (ESCC) remains an obstacle for the effective radiotherapy of ESCC. This study aimed to investigate the radiosensitization of ESCC by signal transducer and activator of transcription 3 (STAT3) inhibitor stattic. ECA109, TE13, and KYSE150 cell lines were exposed to hypoxia and treated with stattic or radiation, alone or in combination. Cell proliferation, colony formation, apoptosis, and double-stranded DNA breaks (DSBs) were examined. In addition, ECA109 cells were xenografted into nude mice and treated with radiation and/or stattic. The levels of STAT3, p-STAT3, hypoxia-inducible factor 1α (HIF-1α), and vascular endothelial growth factor (VEGF) in ESCC cells and xenografts were detected by Western blot and immunohistochemical analysis. Our results showed that stattic efficiently radiosensitized ESCC cells and xenografts, especially under hypoxia. Moreover, stattic inhibited STAT3 activation and downregulated HIF-1α and VEGF expression. In conclusion, stattic confers radiosensitivity in ESCC cells in vitro and in vivo and is a potential adjuvant for the radiotherapy of ESCC in the clinical setting.

MicroRNA-21 is a novel promising target in cancer radiation therapy.

MicroRNAs (miRNAs) represent an important nonprotein part of the human genome in tumor biology. Among the several types of miRNAs, microRNA-21 (miR-21) is dysregulated in several types of cancer and plays a key role in carcinogenesis, recurrence, and metastasis. Thus, it can be a potential target for cancer therapy including radiation therapy. In this review, we focus on miR-21, which has been identified in human cancer tissues, to suggest reasonable strategies for future research. miR-21 may have an influence on cell cycle, DNA damage repair, apoptosis, autophagy, and hypoxia of cancer during irradiation. We review the use of miR-21 in cancer radiation therapy and describe the known functions and possible underlying molecular mechanisms of miR-21 in radiosensitivity and radioresistance. Furthermore, the current and potential future applications of miR-21 in cancer radiation therapy are also discussed.

Melittin enhances radiosensitivity of hypoxic head and neck squamous cell carcinoma by suppressing HIF-1α.

Hypoxia is a widespread phenomenon present in many human solid tumors and is associated with a poor prognosis and therapy resistance. Here, we tested the feasibility of melittin, a major component of bee venom, on radiosensitization of hypoxic head and neck squamous cell carcinoma (HNSCC). CNE-2 and KB cells were treated with melittin and radiation response was determined. Cell viability, cytotoxicity and apoptosis induction were examined by CCK-8 assay, colony formation assay, and flow cytometry. Expression of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF) proteins were assessed using western blotting. Additionally, we also examined the effect of melittin on tumor growth and radiosensitivity in vivo using a xenograft model of HNSCC. Treatment with melittin resulted in cell growth inhibition, induction of cell apoptosis, and reduction of HIF-1α and VEGF expression, which has been linked to hypoxia cell radioresistance. In addition, intraperitoneal injection of melittin significantly reduced the growth of HNSCC tumors in CNE-2 tumor-bearing mice. These data suggest that melittin enhances radiosensitivity of HNSCC under hypoxia condition, and this is associated with the suppression of HIF-1α expression. Melittin appears to be a potential radiotherapy sensitization agent due to its significant antihypoxia activity.