Identification of chemoresistance‐related mRNAs based on gemcitabine‐resistant pancreatic cancer cell lines

Zhou, Jiarong; Zhang, Linshi; Zheng, Huilin; Ge, Weifeng; Huang, Yu; Yan, Yu; Zhou, Xin; Zhu, Wei; Kong, Yahui; Ding, Yuan; Wang, Weilin

doi:10.1002/cam4.2764

Cited by 24 publications

(33 citation statements)

References 38 publications

(66 reference statements)

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“…In contrast, SRSF3 could control the PDGFRB pathway indirectly, by modulating the alternative splicing of five potential regulators of PDGFRB expression such as TFDP1 , CUX1 , PRDM10 , TEAD4 and TP73 . Previously, altered TFDP1 , CUX1 and PRDM10 splicing has been reported to generate variants that act as super enhancers of several oncogenes and cell cycle checkpoint genes ( Rong Zeng et al , 2000 ; Sansregret and Nepveu, 2008 ; Cadieux et al , 2009 ; Park and Kim, 2010 ; Hulea and Nepveu, 2012 ; Ramdzan and Nepveu, 2014 ; Lu et al , 2016 ; Kaur et al , 2018 ; Zhang et al , 2018 ; Chen et al , 2019 a ; Zhou et al , 2020 ), while altered TEAD4 splicing events could result in VEGF inhibition ( Appukuttan et al , 2012 ; Qi et al , 2016 ; Xu et al , 2018 ). Most interestingly, some splicing variants of TP73 (the only factor reported as a PDGFRB regulator from the five identified) can distinctly act as tumour suppressors, arresting the cell cycle and inducing apoptosis ( Liu et al , 2004 ; Jancalek, 2014 ; Vikhreva et al , 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3

Fuentes-Fayos

Vázquez‐Borrego

Jiménez‐Vacas

et al. 2020

Brain

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Glioblastomas remain the deadliest brain tumour, with a dismal ∼12–16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology.

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Section: Discussionmentioning

confidence: 99%

Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3

Fuentes-Fayos

Vázquez‐Borrego

Jiménez‐Vacas

et al. 2020

Brain

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“…Furthermore, it was shown that cells treated with either 5-fluorouracil or gemcitabine increased ORAI1 and STIM1 expression as well as SOC entry suggesting that ORAI1 and STIM1 confer resistance to chemotherapy, probably through the increase of SOC entry (Kondratska et al, 2014). More recently, STIM1 was found to be involved in gemcitabine resistance in PDAC (Zhou et al, 2020). The transcriptome sequencing analysis in established gemcitabine resistant PDAC cell lines, showed that STIM1 was significantly upregulated in the gemcitabine resistant cell lines, compared to the parental cell line (Zhou et al, 2020).…”

Section: Therapeutic Targetsmentioning

confidence: 99%

“…More recently, STIM1 was found to be involved in gemcitabine resistance in PDAC (Zhou et al, 2020). The transcriptome sequencing analysis in established gemcitabine resistant PDAC cell lines, showed that STIM1 was significantly upregulated in the gemcitabine resistant cell lines, compared to the parental cell line (Zhou et al, 2020). Among the chloride channels, knockdown of TMEM16J provided an additive effect on inhibiting proliferation upon treatment with gemcitabine and erlotinib, suggesting that a TMEM16J inhibitor can help to prevent gemcitabine resistance associated with the prolonged use of gemcitabine (Jun et al, 2017).…”

Section: Therapeutic Targetsmentioning

confidence: 99%

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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“…[24][25][26] In the gemcitabine-resistant PDAC models we developed, we observed a tendency to mesenchymal transformation together with increased growth compared with the parental cell lines. These morphological and growth changes, as well as cell cycle arrest in G1 phase, have been already related to drug resistance by Zhou et al, 23 with different features according to the cell type. Moreover, two studies indicated that c-MET signaling and STAT3 activation play an important role in acquired resistance to gemcitabine.…”

Section: Discussionmentioning

confidence: 79%

Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models

Rabia

Garambois

Hubert

et al. 2021

mAbs

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Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabineresistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect in vitro and in mice xenografted with the gemcitabinesensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.

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Identification of chemoresistance‐related mRNAs based on gemcitabine‐resistant pancreatic cancer cell lines

Abstract: Gemcitabine (GEM) alone and GEM-based chemotherapy are the preferred regimens for treating advanced unresectable and metastatic pancreatic cancer (PC). However,

Cited by 24 publications

References 38 publications

Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3

Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models

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