• drug development
• translational research
• target identification

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/drug therapy
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Signal Transduction/drug effects
• Signal Transduction/genetics
• Protein Kinase Inhibitors/therapeutic use
• Immune Checkpoint Inhibitors/therapeutic use

• 82222047, 82073039 National Natural Science Foundation of China (National Science Foundation of China)

• JAK-STAT pathway
• Liver cancer
• Pathogenesis Targeted therapy

• Humans
• Signal Transduction
• Janus Kinases/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/therapy
• STAT Transcription Factors/metabolism
• Animals

• Y202146219 Zhejiang Provincial Department of Education
• 2023SCG250 Zhejiang Provincial Education Science Planning General Planning project
• 20220326 the Postgraduate Education Research Project of Zhejiang University
• 42 Zhejiang University Medical School Education Reform Project

• Hepatocellular carcinoma
• Il-6/STAT3 signaling pathway
• Malignant behaviors
• Prostate apoptosis response protein-4(PAR-4)

• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/genetics
• STAT3 Transcription Factor/metabolism
• Interleukin-6/metabolism
• Humans
• Animals
• Signal Transduction
• Mice, Nude
• Apoptosis Regulatory Proteins/metabolism
• Mice
• Male
• Cell Proliferation
• Cell Movement
• Cell Line, Tumor
• Apoptosis
• Gene Expression Regulation, Neoplastic
• Female

• ALI
• AML-12
• Hepatocyte apoptosis
• PSTPIP2
• STAT3

• Animals
• Male
• Mice
• Adaptor Proteins, Signal Transducing/metabolism
• Adaptor Proteins, Signal Transducing/genetics
• Apoptosis/drug effects
• Cell Line
• Ethanol/toxicity
• Ethanol/administration & dosage
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Liver Diseases, Alcoholic/metabolism
• Liver Diseases, Alcoholic/pathology
• Liver Diseases, Alcoholic/prevention & control
• Mice, Inbred C57BL
• STAT3 Transcription Factor/metabolism
• STAT3 Transcription Factor/genetics

• Ferroptosis
• Hepatocellular carcinoma
• Nf-κB
• SSPH I
• STAT3

• Humans
• Ferroptosis/drug effects
• Hep G2 Cells
• STAT3 Transcription Factor/metabolism
• NF-kappa B/metabolism
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Liver Neoplasms/drug therapy
• Signal Transduction/drug effects
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/drug therapy
• Sulfones/pharmacology
• Nitriles/pharmacology
• Reactive Oxygen Species/metabolism
• Cyclic S-Oxides/pharmacology
• Lipid Peroxidation/drug effects

• 82060793 National Natural Science Foundation of China
• 2021JJB140005 Natural Science Foundation of Guangxi Province
• 2021007 Qihuang Project Team of Guangxi University of Chinese Medicine
• 2022C043 Young talents in Gui Pai Xing lin of Guangxi University of Chinese Medicine

• Cancer stem cell
• Epstein–Barr virus
• Genomic profiling
• Metastasis
• Molecular heterogeneity
• Nasopharyngeal carcinoma
• Personalized medicine
• Precision oncology
• Targeted therapy

• Humans
• Nasopharyngeal Carcinoma
• Epstein-Barr Virus Infections
• Precision Medicine
• Herpesvirus 4, Human/physiology
• Nasopharyngeal Neoplasms

• Ministry of Higher Education, Malaysia
• UCSI University

• Apoptosis
• Autophagy
• Hepatocellular carcinoma
• Qi-Wei-Wan formula
• STAT3 and mTOR signaling

• STAT3
• complement factor H
• endothelial cell
• migration
• vascular endothelial growth factor receptor 2

• Hepatocellular carcinoma
• Liver cancer
• Molecular signaling
• Noncoding transcripts
• STAT3

• Humans
• Carcinogenesis/genetics
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm/genetics
• Gene Expression Regulation, Neoplastic
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• STAT3 Transcription Factor/metabolism

• FRGS/1/2019/SKK08/UKM/02/9 Ministry of Higher Education, Malaysia
• GUP-2020-076 Universiti Kebangsaan Malaysia
• Projekt DEAL

This review article outlines six molecular pathways that confer resistance of cancer cells to ionizing radiation, and describes how proton pump inhibitors (PPIs) may be used to overcome radioresistance induced by alteration of one or more of these signaling pathways. The inflammatory, adaptive, hypoxia, DNA damage repair, cell adhesion, and developmental pathways have all been linked to the resistance of cancer cells to ionizing radiation. Here we describe the molecular link between alteration of these pathways in cancer cells and development of resistance to ionizing radiation, and discuss emerging data on the use of PPIs to favorably modify one or more components of these pathways to sensitize cancer cells to ionizing radiation. Understanding the relationship between altered signaling pathways, radioresistance, and biological activity of PPIs may serve as a basis to repurpose PPIs to restore key biological processes that are involved in cancer progression and to sensitize cancer cells to radiation therapy.

Purpose: To evaluate the feasibility of 4-dimensional magnetic resonance imaging (4DMRI) in establishing the target of primary liver cancer in comparison with 4-dimensional computed tomography (4DCT). Methods and Materials: A total of 23 patients with primary liver cancer who received radiotherapy were selected, and 4DCT and T2w-4DMRI simulations were conducted to obtain 4DCT and T2w-4DMRI simulation images. The 4DCT and T2w-4DMRI data were sorted into 10 and 8 respiratory phase bins, respectively. The liver and gross tumor volumes (GTVs) were delineated in all images using programmed clinical workflows under tumor delineation guidelines. The internal organs at risk volumes (IRVs) and internal target volumes (ITVs) were the unions of all the phase livers and GTVs, respectively. Then, the artifacts, liver volume, GTV, and motion range in 4DCT and T2w-4DMRI were compared. Results: The mean GTV volume based on 4DMRI was 136.42 ± 231.27 cm³, which was 25.04 cm³ (15.5%) less than that of 4DCT (161.46 ± 280.29 cm³). The average volume of ITV determined by 4DMRI was 166.12 ± 270.43 cm³, which was 22.44 cm³ (11.9%) less than that determined by 4DCT (188.56 ± 307.57 cm³). Liver volume and IRV in 4DMRI increased by 4.0% and 6.6%, respectively, compared with 4DCT. The difference in tumor motion by T2w-4DMRI based on the centroid was greater than that of 4DCT in the L/R, A/P, and S/I directions, and the average displacement differences were 2.6, 2.8, and 6.9 mm, respectively. The severe artifacts in 4DCT were 47.8% (11/23) greater than in 4DMRI 17.4% (4/23). Conclusions: Compared with 4DCT, T2-weighted and navigator-triggered 4DMRI produces fewer artifacts and larger motion differences in hepatic intrafraction tumors, which is a feasible technique for primary liver cancer treatment planning.

• 4DCT
• MRI
• liver cancer
• radiotherapy
• respiratory motion simulation
• tumor delineation

• cancer
• drug
• hepatocellular carcinoma
• molecular target
• phytochemicals
• signaling pathway

• Stattic
• cell death
• cervical cancer
• glutathione reductase
• reactive oxygen species
• tumor growth

• CSCs
• Cancer stem cells
• Clinical significance
• Self-renewal
• Targeted therapy
• Treatment resistance

Our objective is to assess whether the outcome of intrahepatic unresectable or ablative hepatocellular carcinoma (HCC) could be improved by supplemental transarterial chemoembolization (TACE) following initial treatment of TACE with 3-dimensional conformal radiotherapy (3DCRT), compared to TACE followed by 3DCRT alone.

We retrospectively analyzed intrahepatic unresectable or ablative HCC patients who underwent TACE, followed by 3DCRT with or without additional TACE, from June 2010 to December 2016 at our institution. Survival was assessed using the Kaplan-Meier method and compared with the log-rank test. Cox regression analyses were used to identify factors that influenced prognosis. Toxicity profiles were evaluated using CTCAE 4.0.

27 patients received TACE with 3DCRT (TR group) and 11 received additional TACE following TACE and 3DCRT (sandwich group), respectively. The median intrahepatic progression-free survival (IPFS), progression-free survival (PFS), and overall survival (OS) in the TR group and sandwich group were 5.4 months vs. 17 months (P = 0.018), 5.4 months vs. 17 months (P = 0.008), and 13.5 months vs. 29.2 months (P = 0.011), respectively. Multivariate Cox regression demonstrated that TACE followed by radiotherapy alone had a shorter IPFS (HR: 2.516, 95% CI (1.136-5.570), P = 0.023) and PFS (HR: 2.637, 95% CI (1.182-5.880), P = 0.018) compared with the sandwich treatment. Hepatitis B virus reactivation occurred in 1 patient in the sandwich group. Myleosuppresion was considered a grade 3/4 adverse event.

Unresectable or ablative HCC patients possibly benefit from the combination of TACE and 3DCRT followed by additional TACE therapy, compared with TACE followed by 3DCRT alone.

• hepatocellular carcinoma
• radiotherapy
• sandwich treatment
• survival
• transarterial chemoembolization

• HCC
• carcinogenesis
• genomics
• liver cancer
• mutation
• therapeutics

• K08 CA222676 NCI NIH HHS

• STAT3
• STAT3β
• chemoresistance
• radioresistance
• target therapy

Esophageal cancer is a common digestive tract tumor that is generally treated with radiotherapy. Poor responses to radiotherapy in most patients generally result in local radiotherapy failure, so it is essential to find new radiosensitizers that can enhance the response of cancer cells to radiotherapy and improve the survival of esophageal cancer patients with radiation resistance. The long non-coding RNA (lncRNA) Rpph1 is highly expressed in human gastric cancer tissues, and represses breast cancer cell proliferation and tumorigenesis. However, the expression of lncRNA Rpph1 in esophageal cancer and its relationship with radio-sensitivity has not been studied.

To explore the value of lncRNA Rpph1 in esophageal cancer and its effect on cancer cell sensitivity to radiotherapy.

Eighty-three patients with esophageal cancer admitted to Qilu Hospital of Shandong University and 90 healthy participants who received physical examinations were collected as research participants. The expression of Rpph1 was determined by qRT-PCR. siRNA-NC and siRNA-Rpph1 were transfected into esophageal cancer cell lines, and cells without transfection were designated as the blank control group. Cell survival was tested by colony formation assays, and the levels of proteins related to apoptosis and epithelial-mesenchymal transitions were determined by Western blot assays. Cell proliferation was assessed by MTT assays, cell apoptosis by flow cytometry, and cell migration by wound-healing assays. Changes in cell cycle distribution were monitored.

Rpph1 was highly expressed in esophageal carcinoma, making it a promising marker for the diagnosis of esophageal cancer. Rpph1 could also be used to distinguish different short-term responses, T stages, N stages, and clinical stages of esophageal cancer patients. The results of 3-year overall survival favored patients with lower Rpph1 expression over patients with higher Rpph1 expression (P < 0.05). In vitro and in vivo experiments showed that silencing Rpph1 expression led to higher sensitivity of esophageal cancer cells to radiotherapy, stronger apoptosis in esophageal cancer cells induced by radiotherapy, higher expression of Bax and caspase-3, and lower expression of Bcl-2 (Bax, caspase-3, and Bcl-2 are apoptosis-related proteins). Additionally, silencing Rpph1 attenuated radiation-induced G2/M phase arrest, and significantly inhibited the expression of proteins involved in cell proliferation, migration, and epithelial-mesenchymal transition regulation in esophageal cancer cells.

Rpph1 is highly expressed in esophageal cancer. Silencing Rpph1 expression can promote cell apoptosis, inhibit cell proliferation and migration, and increase radio-sensitivity.

• Long non-coding RNA Rpph1
• Esophageal cancer
• Cell sensitivity to radiotherapy
• Apoptosis
• Cell cycle
• Epithelial-mesenchymal transition

• Adenocarcinoma/genetics
• Adenocarcinoma/mortality
• Adenocarcinoma/pathology
• Adenocarcinoma/radiotherapy
• Aged
• Apoptosis/genetics
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Epithelial-Mesenchymal Transition/genetics
• Esophageal Neoplasms/genetics
• Esophageal Neoplasms/mortality
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/radiotherapy
• Esophageal Squamous Cell Carcinoma/genetics
• Esophageal Squamous Cell Carcinoma/mortality
• Esophageal Squamous Cell Carcinoma/pathology
• Esophageal Squamous Cell Carcinoma/radiotherapy
• Female
• Follow-Up Studies
• G2 Phase Cell Cycle Checkpoints/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Middle Aged
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• RNA, Small Interfering/metabolism
• Radiation Tolerance/genetics
• Treatment Outcome

This study aimed to investigate the clinicopathologic features and mutational landscape of patients with hepatitis B virus (HBV)–related advanced hepatocellular carcinomas (HCC) undergoing transcatheter arterial chemoembolization (TACE).

From January 2017 to December 2018, 38 patients newly diagnosed with HBV-related advanced HCC were enrolled in the final analysis. Their pathological tissues and corresponding blood samples before TACE treatment were collected for whole-exome sequencing. Response to TACE was evaluated at 1-3 months after two consecutive use of TACE. Predictive factors were analyzed by univariate and multivariate analyses in a bivariate Logistic regression model. Enrichment of related pathways of all driver genes were acquired using the gene set enrichment analysis (GSEA).

Among 38 patients, 23 (60.5%) exhibited TACE failure/refractoriness. Patients with TACE failure/refractoriness showed higher frequency of TP53 mutation than their counterparts (p=0.020). Univariate and multivariate analyses showed that only vascular invasion and TP53 mutation were significantly correlated with TACE failure/refractoriness in HBV-related advanced HCC. Of the 16 patients without vascular invasion, eight (50.0%) had TP53 mutations, and TP53 mutation was associated with TACE failure/refractoriness (p=0.041). Moreover, GSEA showed that mitogen-activated protein kinase and apoptosis pathways induced by TP53 mutation were possibly associated with TACE failure/refractoriness.

Our study suggested that TP53 mutation was independently related with TACE efficacy, which may work via mitogen-activated protein kinase and apoptosis pathways. These findings may provide evidence to help distinguish patients who will particularly benefit from TACE from those who require more personalized therapeutic regimens and rigorous surveillance in HBV-related advanced HCC.

• Hepatocellular carcinoma
• Transcatheter arterial chemoembolization
• Treatment outcome
• Tumor protein p53
• Tumor response
• Whole-exome sequencing

• JAK/STAT signaling
• hepatocarcinogenesis
• hepatocellular carcinoma
• liver cancer
• targeted therapy

• IRX5
• apoptosis
• hepatocellular carcinoma
• p53 signalling pathway
• proliferation

• Nrf2 inhibitor
• chemosensitizer
• multidrug resistance

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation.

• Ac-RelA/p65
• Lambertianic acid
• NF-κB
• STAT3
• p300