Jonckheere, N. | bioRxiv Science

bioRxiv2024

Long non-coding RNA UCA1 affects chromatin remodeling via SMARCA2-containing SWI/SNF complex in human colorectal cancer.

Differential lncRNA expression has been correlated to clinical characteristics of colorectal cancers (CRC), which are the second leading cause of cancer-related deaths. LncRNA UCA1 plays a role in epigenetic gene regulation in diverse cancers. We studied CRC cell properties in CRISPR/Cas9 HT29-derived models and, interestingly, UCA1-depleted HT29 cells presented an increased stem-cell phenotype. We show that loss of UCA1 affected SWI/SNF chromatin remodeling complexes, which are previously shown to be involved in maintaining stem-cell properties. Not only was UCA1 permissive for induced SWI/SNF subunit SMARCA2 (BRM) expression upon chemo-drug treatment, but it also affected subunit compositions of SWI/SNF complexes by direct interaction of UCA1 with both ATP helicase BRM and BRG1. UCA1 is known to stimulate proliferation and decrease apoptosis, and we here show that it can restrain cells from a stem cell phenotype. The dual action of UCA1 revealed in this study highlights the complex actions of lncRNAs in cancer.

cancer biology↗

bioRxiv2018

TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the western countries because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cell also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatment for PDAC.\n\nTGF-{beta} possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-{beta} signalling pathway plays complex role during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as tumor suppressor pathway. TGF-{beta} binds to its receptor TGF-{beta}RII and activates different pathways: canonical pathway involving the Smad proteins and alternative pathways such as MAPKs. Smad4 is mutated in 50-80% of PDAC. Mutations of TGF-{beta}RII also occurs (5-10%). In order to decipher the role of TGF-{beta} in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-{beta}RII that is the first actor of TGF-{beta} signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-{beta}RII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-{beta}RII silencing alters tumor growth and migration as well as resistance to. TGF-{beta}RII silencing also leads to S727 STAT3 and S-63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype.\n\nIn the future, the better understanding TGF-{beta} signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.

cancer biology↗