Background Long non-coding RNAs (lncRNA) have an essential role in progression and chemoresistance of hepatocellular carcinoma (HCC). In-depth study of specific regulatory mechanisms is of great value in providing potential therapeutic targets. The present study aimed to explore the regulatory functions and mechanisms of lncRNA TINCR in HCC progression and oxaliplatin response. Methods The expression of TINCR in HCC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration, invasion, and chemosensitivity were evaluated by cell counting kit 8 (CCK8), colony formation, transwell, and apoptosis assays. Luciferase reporter assays and RNA pulldown were used to identify the interaction between TINCR and ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) via miR-195-3p. The corresponding functions were verified in the complementation test and in vivo animal experiment. Results TINCR was upregulated in HCC and associated with poor patient prognosis. Silencing TINCR inhibited HCC proliferation, migration, invasion, and oxaliplatin resistance while overexpressing TINCR showed opposite above-mentioned functions. Mechanistically, TINCR acted as a competing endogenous (ceRNA) to sponge miR-195-3p, relieving its repression on ST6GAL1, and activated nuclear factor kappa B (NF-κB) signaling. The mouse xenograft experiment further verified that knockdown TINCR attenuated tumor progression and oxaliplatin resistance in vivo. Conclusions Our finding indicated that there existed a TINCR/miR-195-3p/ST6GAL1/NF-κB signaling regulatory axis that regulated tumor progression and oxaliplatin resistance, which might be exploited for anticancer therapy in HCC.

Molecular clocks are the basis for dating the divergence between lineages over macro-evolutionary timescales (~10^5-10^8 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes possess a clock-like behavior. This "epimutation-clock" is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation-clocks recapitulate known topologies and branching times of intra-species phylogenetic trees in the selfing plant A. thaliana and the clonal seagrass Z. marina, which represent two major modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.

Background: Combination treatment with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has been widely used in patients with unresectable hepatocellular carcinoma (uHCC). As no standard guidelines exist for second-line therapy after failure of combination treatment, this study aimed to determine a better drug-switching strategy.Methods: A total of 785 patients with uHCC who initially received a combination treatment of TKIs and ICIs between January 2017 and December 2021 at our center were screened. After applying the inclusion and exclusion criteria, a total of 102 patients were included in the study. Based on drug switching strategy, patients were divided into a single drug-switching group (A group, n = 49) and a double drug-switching group (B group, n = 53). The comparative effectiveness between groups A and B was assessed based on treatment response and survival time. Second progression-free survival (SPFS) and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test.Results: Compared to group B, group A had a higher overall response rate (16.3% vs. 3.8%; p = 0.0392) and disease control rate (61.2% vs. 49.1%; p = 0.238). The median SPFS in group A was longer than that in group B (5.47 vs. 3.8 months; HR = 1.70, p = 0.0176). In the second-line therapy, the inclusion of lenvatinib resulted in a better SPFS than other TKI treatments (5.53 vs. 2.83 months, p = 0.0038).Conclusion: After the failure of the combination treatment of TKIs and ICIs, single-drug switching significantly prolonged median SPFS in uHCC patients, and retaining lenvatinib resulted in the survival benefit of single-drug switching.