Biological and pharmacological roles of m6A modifications in cancer drug resistance.

Cancer drug resistance represents the main obstacle in cancer treatment. Drug-resistant cancers exhibit complex molecular mechanisms to hit back therapy under pharmacological pressure. As a reversible epigenetic modification, N6-methyladenosine (m6A) RNA modification was regarded to be the most common epigenetic RNA modification. RNA methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers) are frequently disordered in several tumors, thus regulating the expression of oncoproteins, enhancing tumorigenesis, cancer proliferation, development, and metastasis. The review elucidated the underlying role of m6A in therapy resistance. Alteration of the m6A modification affected drug efficacy by restructuring multidrug efflux transporters, drug-metabolizing enzymes, and anticancer drug targets. Furthermore, the variation resulted in resistance by regulating DNA damage repair, downstream adaptive response (apoptosis, autophagy, and oncogenic bypass signaling), cell stemness, tumor immune microenvironment, and exosomal non-coding RNA. It is highlighted that several small molecules targeting m6A regulators have shown significant potential for overcoming drug resistance in different cancer categories. Further inhibitors and activators of RNA m6A-modified proteins are expected to provide novel anticancer drugs, delivering the therapeutic potential for addressing the challenge of resistance in clinical resistance.

Omics-based molecular classifications empowering in precision oncology.

BACKGROUND: In the past decades, cancer enigmatical heterogeneity at distinct expression levels could interpret disparities in therapeutic response and prognosis. It built hindrances to precision medicine, a tactic to tailor customized treatment informed by the tumors' molecular profile. Single-omics analysis dissected the biological features associated with carcinogenesis to some extent but still failed to revolutionize cancer treatment as expected. Integrated omics analysis incorporated tumor biological networks from diverse layers and deciphered a holistic overview of cancer behaviors, yielding precise molecular classification to facilitate the evolution and refinement of precision medicine. CONCLUSION: This review outlined the biomarkers at multiple expression layers to tutor molecular classification and pinpoint tumor diagnosis, and explored the paradigm shift in precision therapy: from single- to multi-omics-based subtyping to optimize therapeutic regimens. Ultimately, we firmly believe that by parsing molecular characteristics, omics-based typing will be a powerful assistant for precision oncology.

Proteomics appending a complementary dimension to precision oncotherapy.

Recent advances in high-throughput proteomic profiling technologies have facilitated the precise quantification of numerous proteins across multiple specimens concurrently. Researchers have the opportunity to comprehensively analyze the molecular signatures in plentiful medical specimens or disease pattern cell lines. Along with advances in data analysis and integration, proteomics data could be efficiently consolidated and employed to recognize precise elementary molecular mechanisms and decode individual biomarkers, guiding the precision treatment of tumors. Herein, we review a broad array of proteomics technologies and the progress and methods for the integration of proteomics data and further discuss how to better merge proteomics in precision medicine and clinical settings.

Op18/stathmin is involved in the resistance of taxol among different epithelial carcinoma cell lines.

PURPOSE: Taxol is an effective chemotherapeutic agent against epithelial-derived carcinomas, and resistance of carcinoma cells to taxol has developed with the wide prescription of the drug. In this study, five different epithelial carcinoma cell lines were randomly employed to screen the resistant cell line to taxol, and to explore the probable mechanism of taxol-resistant development. MATERIALS AND METHODS: Cells were grouped into the controls and the taxol treated. The treatment effects of five different epithelial carcinoma cell lines, including CNE1, Hep3B-2, MGC, MCF-7, and NCI-H1299, after being treated by taxol were analyzed through inspecting the ratios of cellular apoptosis, inhibition of cellular proliferation, the capability of cell colony formation and wound recovery, and the interference of cell motility and invasion, while western blot analysis and siRNA targeting Op18/stathmin were applied to explore the probable mechanism on the taxol resistance difference in these cells. RESULTS: Nonsmall cell lung cancer NCI-H1299 cells presented obvious taxol resistance, and the inhibition of cell motility and invasion was also the weakest in taxol-treated NCI-H1299 cells among these five cell lines. Microtubule dynamics analysis demonstrated that taxol treatment destroyed normal microtubule arrays and caused obvious microtubule collapse in CNE1, Hep3B-2, MGC, and MCF-7 rather than NCI-H1299, while the latter expressed high levels of microtubule-destabilizing protein Op18/stathmin. Inhibition of Op18/stathmin expression increased the sensitivity to taxol and promoted cellular apoptosis in NCI-H1299 cells. CONCLUSION: NCI-H1299 cells are evidently resistant to taxol-induced cellular apoptosis, inhibition of cellular proliferation and wound recovery, as well as cell migration and invasion interference, which are closely associated with the changes of microtubule dynamics. High expression of Op18/stathmin is perhaps a crucial determinant of taxol-resistant development in NCI-H1299 cells.