Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair

Zhang, Xiang; Zheng, Shusen; Hu, Chonghui; Li, Guolin; Lin, Hongcao; Xia, Renpeng; Ye, Yuancheng; He, Rihua; Li, Zhihua; Q, Lin; Chen, Rufu; Zhou, Quanbo

doi:10.1038/s41388-022-02253-6

Cited by 40 publications

(23 citation statements)

References 61 publications

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“…Zhang et al also reported that higher IL-8 production by PDAC CAFs is correlated with oxaliplatin resistance in these patients. The underlying mechanism of this chemoresistance was attributed to the upregulation of UPK1A-AS1 lncRNA via IL-8 signaling, which in turn enhances DNA double-strand break (DSB) repair by strengthening the binding between Ku70 and Ku80 (52). Furthermore, it has been reported that CAFs can induce 5-FU resistance in colorectal cancer through cargo delivery of secreted exosomes (53).…”

Section: Discussionmentioning

confidence: 99%

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

et al. 2022

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Pancreatic cancer is a lethal malignancy with a 5-year survival rate of about 10% in the United States, and it is becoming an increasingly prominent cause of cancer death. Among pancreatic cancer patients, pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all cases and has a very poor prognosis with an average survival of only 1 year in about 18% of all tumor stages. In the past years, there has been an increasing interest in cancer-associated fibroblasts (CAFs) and their roles in PDAC. Recent data reveals that CAFs in PDAC are heterogeneous and various CAF subtypes have been demonstrated to promote tumor development while others hinder cancer proliferation. Furthermore, CAFs and other stromal populations can be potentially used as novel prognostic markers in cancer. In the present study, in order to evaluate the prognostic value of CAFs in PDAC, CAF infiltration rate was evaluated in 4 PDAC datasets of TCGA, GEO, and ArrayExpress databases and differentially expressed genes (DEGs) between CAF-high and CAF-low patients were identified. Subsequently, a CAF-based gene expression signature was developed and studied for its association with overall survival (OS). Additionally, functional enrichment analysis, somatic alteration analysis, and prognostic risk model construction was conducted on the identified DEGs. Finally, oncoPredict algorithm was implemented to assess drug sensitivity prediction between high- and low-risk cohorts. Our results revealed that CAF risk-high patients have a worse survival rate and increased CAF infiltration is a poor prognostic indicator in pancreatic cancer. Functional enrichment analysis also revealed that “extracellular matrix organization” and “vasculature development” were the top enriched pathways among the identified DEGs. We also developed a panel of 12 genes, which in additional to its prognostic value, could predict higher chemotherapy resistance rate. This CAF-based panel can be potentially utilized alone or in conjunction with other clinical parameters to make early predictions and prognosticate responsiveness to treatment in PDAC patients. Indeed, it is necessary to conduct extensive prospective investigations to confirm the clinical utility of these findings.

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Section: Discussionmentioning

confidence: 99%

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

et al. 2022

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“…Platinum-based chemotherapy is a first-line chemotherapy treatment for patients with advanced pancreatic cancer; however, the overall response rate is only 30% worldwide ( 21 ). Our previous study reported that cancer-associated fibroblasts promote the acquired oxaliplatin resistance of pancreatic cancer cells via paracrine signaling ( 22 ). However, there are few studies on the inherent oxaliplatin resistance of pancreatic cancer tumor cells ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

HNF1A regulates oxaliplatin resistance in pancreatic cancer by targeting 53BP1

Xia

et al. 2023

Int J Oncol

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DNA double-strand break repair is critically involved in oxaliplatin resistance in pancreatic ductal adenocarcinoma (PDAC). Hepatocyte nuclear factor 1 homeobox A (HNF1A) has received increased attention regarding its role in cancer progression. The present study explored the role of HNF1A in oxaliplatin resistance in PDAC. The results revealed that HNF1A expression was negatively associated with oxaliplatin chemoresistance in PDAC tissues and cell lines. HNF1A inhibition promoted the proliferation, colony formation and stemness of PDAC cells, and suppressed their apoptosis. Furthermore, HNF1A inhibition switched nonhomologous end joining to homologous recombination, thereby enhancing genomic stability and oxaliplatin resistance. Mechanistically, HNF1A transcriptionally activates p53-binding protein 1 (53BP1) expression by directly interacting with the 53BP1 promoter region. Upregulation of HNF1A and 53BP1 induced significant inhibition of PDAC growth and oxaliplatin resistance in patient-derived PDAC xenograft models and orthotopic models. In conclusion, the findings of the present study suggested that HNF1A/53BP1 may be a promising PDAC therapeutic target for overcoming oxaliplatin resistance.

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“…LINC01426 knockdown dramatically decreased pancreatic cancer cell growth in vivo. S e v e r a l c l i n i c a l a n d b a s i c i n v e s t i g a t i o n s h a v e demonstrated that lncRNAs are implicated in molecular mechanisms (16)(17)(18). Some lncRNAs regulate the incidence and development of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical and basic investigations have demonstrated that lncRNAs are implicated in molecular mechanisms ( 16 - 18 ). Some lncRNAs regulate the incidence and development of pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of LINC01426 inhibits the proliferation and migration of human pancreatic cancer cells in vivo and in vitro

Ming

Zhang

et al. 2022

J Gastrointest Oncol

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Background: We performed in vivo and in vitro experiments to observe the expression of long intergenic nonprotein coding RNA 1426 (LINC01426) in pancreatic cancer tissues and cells, investigate the impact of LINC01426 on the proliferation and migration of pancreatic cancer cells, and deduce the underlying molecular mechanism.Methods: LINC01426 expression was measured by fluorescence-based quantitative polymerase chain reaction (PCR) in pancreatic cancer tissues and cell lines. The lentiviral vector was used to create shRNA-NC, shLINC01426#2, pcDNA-NC, and pcDNA-LINC01426 pancreatic cancer cell lines. Cell Counting Kit-8 (CCK-8), clonogenic, and scratch tests were used to measure the effects of LINC01426 knockdown or overexpression on the migration and proliferation of pancreatic cancer cells. The expression levels of genes involved in migration (E-cadherin, N-cadherin, and vimentin) were examined by Western blotting after LINC01426 was either knocked down or overexpressed. The effect of LINC01426 knockdown on the proliferation of pancreatic cancer cells in vivo was verified in nude mice.Results: LINC01426 was highly expressed in pancreatic cancer cells and tissues. Overexpression of LINC01426 might have promoted the proliferation, clonogenicity, and migration of pancreatic cancer cells, while knockdown of LINC01426 decreased these activities. In pancreatic cancer cells, knockdown of LINC01426 dramatically enhanced E-cadherin expression while lowering N-cadherin and vimentin expression, whereas overexpression of LINC01426 had the opposite effect. Knockdown of LINC01426 substantially decreased pancreatic cancer cell proliferation in an in vivo study.Conclusions: Overexpression of LINC01426 was shown to increase the migration and proliferation of pancreatic cancer cells in both in vivo and in vitro experiments. LINC01426 could be a novel predictive biomarker and source of prospective therapeutic targets for patients with pancreatic cancer.

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Cancer-associated fibroblast-induced lncRNA UPK1A-AS1 confers platinum resistance in pancreatic cancer via efficient double-strand break repair

Cited by 40 publications

References 61 publications

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

HNF1A regulates oxaliplatin resistance in pancreatic cancer by targeting 53BP1

Downregulation of LINC01426 inhibits the proliferation and migration of human pancreatic cancer cells in vivo and in vitro

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