Non-coding RNA and Drug resistance in cholangiocarcinoma.

Cholangiocarcinoma is a highly aggressive cancer with a dismal prognosis and limited resectability. Chemotherapy has demonstrated tremendous benefits for patients with advanced and inoperable cancer, but drug resistance poses a significant obstacle. Despite recent progress in cancer therapy, the mechanisms driving drug resistance are multifaceted and not completely comprehended. Non-coding RNA refers to RNA molecules that are endogenous and do not code for proteins. Particularly microRNAs, long non-coding RNAs, circular RNAs, are widely acknowledged to be involved in cancer initiation, proliferation, and metastasis. Recently, evidences suggests that abnormal expression of non-coding RNAs contributes to resistance to different type of cancer therapies in cholangiocarcinoma. This occurs via the rewiring of signaling pathways including the reduction of anticancer drugs, apoptosis, interaction between cholangiocarcinoma and tumor-infiltrating immune cells, and cancer stemness. Thus, our review aims to demonstrate the potential of targeting non-coding RNA to override drug resistance and summarize the molecular mechanisms of how non-coding RNA contributes to drug resistance in cholangiocarcinoma.

BacPE: a versatile prime-editing platform in bacteria by inhibiting DNA exonucleases.

Prime editing allows precise installation of any single base substitution and small insertions and deletions without requiring homologous recombination or double-strand DNA breaks in eukaryotic cells. However, the applications in bacteria are hindered and the underlying mechanisms that impede efficient prime editing remain enigmatic. Here, we report the determination of vital cellular factors that affect prime editing in bacteria. Genetic screening of 129 Escherichia coli transposon mutants identified sbcB, a 3'→5' DNA exonuclease, as a key genetic determinant in impeding prime editing in E. coli, combinational deletions of which with two additional 3'→5' DNA exonucleases, xseA and exoX, drastically enhanced the prime editing efficiency by up to 100-fold. Efficient prime editing in wild-type E. coli can be achieved by simultaneously inhibiting the DNA exonucleases via CRISPRi. Our results pave the way for versatile applications of prime editing for bacterial genome engineering.