KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages

Abstract

Tumor microenvironment (TME) exerts key roles in pancreatic ductal adenocarcinoma (PDAC) development. However, the factors regulating the crosstalk between PDAC cells and TME are largely unknown. In this study, we identified a long noncoding RNA (lncRNA) KLHDC7B-DT, which was upregulated in PDAC and correlated with poor survival of PDAC patients. Functional assays demonstrated that KLHDC7B-DT enhanced PDAC cell proliferation, migration, and invasion. Mechanistically, KLHDC7B-DT was found to directly bind IL-6 promoter, induce open chromatin structure at IL-6 promoter region, activate IL-6 transcription, and upregulate IL-6 expression and secretion. The expression of KLHDC7B-DT was positively correlated with IL-6 in PDAC tissues. Via inducing IL-6 secretion, KLHDC7B-DT activated STAT3 signaling in PDAC cells in an autocrine manner. Furthermore, KLHDC7B-DT also activated STAT3 signaling in macrophages in a paracrine manner, which induced macrophage M2 polarization. KLHDC7B-DT overexpressed PDAC cells-primed macrophages promoted PDAC cell proliferation, migration, and invasion. Blocking IL-6/STAT3 signaling reversed the effects of KLHDC7B-DT on macrophage M2 polarization and PDAC cell proliferation, migration, and invasion. In conclusion, KLHDC7B-DT enhanced malignant behaviors of PDAC cells via IL-6-induced macrophage M2 polarization and IL-6-activated STAT3 signaling in PDAC cells. The crosstalk between PDAC cells and macrophages induced by KLHDC7B-DT represents potential therapeutic target for PDAC.

Chromatin accessibility and transcriptome integrative analysis revealed AP-1-mediated genes potentially modulate histopathology features in psoriasis

“…Our findings implicated various aspects of the occurrence and development, including the dysfunction of keratinocyte proliferation and apoptosis, the destruction of the skin barrier, abnormal immune inflammatory response. Among 57 AP-1 targets, KLHDC7B, CDCP1, ID1, E2F8, EIF4E, CALML3, RAP2B, MYO1B are all associated with cell enhanced proliferation, especially in cancer [ 19 – 28 ]. These genes presented a novel possibility in the abnormal proliferation of psoriasis facilitated by AP-1.…”

Hypoxia-Related Long Non-Coding RNA Signature Predicts the Prognosis of Breast Cancer

“…Results from a related study suggest that TFAP2A-AS1 acts as a tumour suppressor in BC via the miR-933/SMAD2 axis 58 .lncLINC01929 accelerates the progression of oral squamous cell carcinoma by targeting the miR-137-3p/FOXC1 axis and is associated with survival in the TCGA dataset [59][60][61] . The high expression of KLHDC7B-DT aggravates pancreatic ductal adenocarcinoma development via inducing cross-talk between cancer cells and macrophages 62 . Immune-associated lncRNA AL133467.1, was identi ed as a predictivefactor with signi cant prognostic value in ovarian carcinoma, corresponding to long survival 63 .Similar to our study, Lai et al reported that they had utilized AC004585.1 and two risk parameters (tumour subtype and TNM stage)as independent indicators to develop a novel prognostic model in breast cancer patients 64 .…”

Missing links — epigenetic regulators of the pancreatic cancer–associated inflammation

“…Thus, further exploring histone deacetylase (HDAC) inhibitors, hypomethylating agents and their combinations, which can shift myeloid and lymphoid cell polarization and cytokine production, offer an intriguing field to explore in clinical trials. The data by Li et al [23] add to the growing body of evidence that the epigenome regulates multiple tumor-supporting pathways in different cell compartments, culminating in a dysregulated immune response in PDAC. Leveraging epigenetics to unleash potential therapeutic benefits of immunotherapy in pancreatic cancer may offer an exceptionally effective way to enhance treatment efficacy and improve the dismal prognosis of pancreatic cancer.…”

“…The findings by Li and colleagues [23] demonstrate a critical new role for lncRNAs in PDAC by offering mechanistic insight into how PDAC leverages epigenetic mechanisms to create a chronically inflamed TME, which supports tumor growth while priming an immune suppressive milieu. This is of particular relevance since chronic but ineffective inflammation is considered a cornerstone of pancreatic oncogenesis.…”

“…In their work presented in Clinical Science, Li and colleagues [23] identify a novel lncRNA KLHDC7B divergent transcript (KLHDC7B-DT) that was highly expressed in human PDAC and correlated with worse disease-free and overall survival. Interestingly, KLHDC7B-DT expression was positively correlated with increasing tumor size and more advanced stages, suggesting a supportive role during disease progression.…”