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The insidious clinical symptoms of pancreatic cancer (PACA), extensive tolerance to radiotherapy and chemotherapy, and insensitivity to immunotherapy result in an inferior prognosis. Redox dyshomeostasis could trigger programmed cell death and contribute to functional changes in immune cells, which is strongly associated with tumorigenesis and tumor development. Therefore, it is warranted to decipher the crosstalk between regulated cell death and immunity in the context of redox dyshomeostasis for PACA. Herein, four redox-related subtypes of PACA were identified: C1 and C2 displayed malignant phenotypes with dismal clinical outcomes, conspicuous enrichment in cell death pathways, high redox score, low immune activation, and "immune-desert" tumor immune microenvironment (TIME); C3, an immune-rejection/excluded subtype, with abundant immune cells, high co-stimulatory, co-inhibitory, and MHC molecules, and potential response to immunotherapy; C4, with the best prognosis, low redox pattern, high level of autophagy, low enrichment of most cell death-related pathways, and "immune-hot" TIME. Overall, this study found an attractive platform from the perspective of redox-related pathways, which would propose insights into the intricate and elaborate molecular mechanisms of PACA and offer more effective and tailored intervention protocols. • The higher basal oxidative state in PACA was related to higher programmed cell death signals, conducting an "immune-cold" TIME. • Relatively low levels of redox state portended favorable clinical outcomes in PACA patients. • ROS manipulation treatment may be a novel potential therapeutic approach for C1 and C2 patients. [ABSTRACT FROM AUTHOR]

Chemoresistance is one of the main obstacles in the therapy of human cancers, including colorectal cancer (CRC). Long non-coding RNA heart and neural crest derivatives expressed 2-antisense RNA 1 (lncRNA HAND2-AS1) has been demonstrated to be associated with CRC. However, the function of HAND2-AS1 in 5-Fluorouracil (5-FU) resistance of CRC remains unclear. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HAND2-AS1, miR-20a and programmed cell death factor 4 (PDCD4) mRNA. 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was conducted to evaluate IC50 of 5-FU and cell proliferation. Flow cytometry analysis was used to determine cell apoptosis. Transwell assay was carried out to measure cell migration and invasion. Western blot assay was conducted to examine the protein levels of B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), matrix metalloprotein 2 (MMP2), MMP9 and PDCD4. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull down assay were utilized to verify the combination between miR-20a and HAND2-AS1. Dual-luciferase reporter assay was used to analyze the association between miR-20a and PDCD4. Murine xenograft assay was used to confirm the function of HAND2-AS1 in vivo. HAND2-AS1 and PDCD4 were downregulated and miR-20a was upregulated in 5-FU-resistant CRC tissues and cells. HAND2-AS1 suppressed 5-FU resistance, cell proliferation, migration and invasion and promoted cell apoptosis in 5-FU-resistant CRC cells. HAND2-AS1 acted as a sponge of miR-20a to regulate PDCD4 expression. Moreover, HAND2-AS1 suppressed cell progression and 5-FU resistance by upregulating PDCD4 via sponging miR-20a in 5-FU-resistant CRC cells. Besides, HAND2-AS1 inhibited tumor growth in vivo. HAND2-AS1/miR-20a/PDCD4 axis inhibited cell progression and 5-FU resistance in 5-FU-resistant CRC cells. • HAND2-AS1, miR-20a and PDCD4 are dysregulated in 5-FU-resistant colorectal cancer tissues and cells. • HAND2-AS1 inhibits 5-FU resistance in 5-FU-resistant colorectal cancer cells. • HAND2-AS1 is a sponge of miR-20a and PDCD4 is a target of miR-20a in 5-FU-resistant colorectal cancer cells. • HAND2-AS1 suppresses 5-FU resistance by regulating miR-20a/PDCD4 axis in colorectal cancer cells. • HAND2-AS1 represses tumor growth in vivo. [ABSTRACT FROM AUTHOR]