TKT-PARP1 axis induces radioresistance by promoting DNA double-strand break repair in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) stands as the fifth most prevalent malignant tumor on a global scale and presents as the second leading cause of cancer-related mortality. DNA damage-based radiotherapy (RT) plays a pivotal role in the treatment of HCC. Nevertheless, radioresistance remains a primary factor contributing to the failure of radiation therapy in HCC patients. In this study, we investigated the functional role of transketolase (TKT) in the repair of DNA double-strand breaks (DSBs) in HCC. Our research unveiled that TKT is involved in DSB repair, and its depletion significantly reduces both non-homologous end joining (NHEJ) and homologous recombination (HR)-mediated DSB repair. Mechanistically, TKT interacts with PARP1 in a DNA damage-dependent manner. Furthermore, TKT undergoes PARylation by PARP1, resulting in the inhibition of its enzymatic activity, and TKT can enhance the auto-PARylation of PARP1 in response to DSBs in HCC. The depletion of TKT effectively mitigates the radioresistance of HCC, both in vitro and in mouse xenograft models. Moreover, high TKT expression confers resistance of RT in clinical HCC patients, establishing TKT as a marker for assessing the response of HCC patients who received cancer RT. In summary, our findings reveal a novel mechanism by which TKT contributes to the radioresistance of HCC. Overall, we identify the TKT-PARP1 axis as a promising potential therapeutic target for improving RT outcomes in HCC.

The cancer-testis lncRNA LINC01977 promotes HCC progression by interacting with RBM39 to prevent Notch2 ubiquitination.

Cancer-testis genes are involved in the occurrence and development of cancer, but the role of cancer-testis-associated lncRNAs (CT-lncRNAs) in hepatocellular carcinoma (HCC) remains to be explored. Here, we discovered a novel CT-lncRNA, LINC01977, based on the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases. LINC01977 was exclusively expressed in testes and highly expressed in HCC. High LINC01977 levels correlated with poorer overall survival (OS) in individuals with HCC. Functional assays showed that LINC01977 promoted HCC growth and metastasis in vitro and in vivo. Mechanistically, LINC01977 directly bound to RBM39 to promote the further entry of Notch2 into the nucleus, thereby preventing the ubiquitination and degradation of Notch2. Furthermore, the RNA binding protein IGF2BP2, one of the m6A modification readers, enhanced the stability of LINC01977, resulting in its high level in HCC. Therefore, the data suggest that LINC01977 interacts with RBM39 and promotes the progression of HCC by inhibiting Notch2 ubiquitination and degradation, indicating that LINC01977 may be a potential biomarker and therapeutic target for HCC patients.

MSH6 Aggravates the Hypoxic Microenvironment via Regulating HIF1A to Promote the Metastasis of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is characterized by diffuse infiltration of the brain, active regional recurrence, low cure proportion, and limited chemotherapy efficiency. MutS homolog 6 (MSH6) is a component of the mismatch repair system related to the oncogenesis, tumor evolution, and recurrence of GBM. The impact of MSH6 upregulation on the tumor microenvironment (TME) of GBM and the feasibility of MSH6 as a potential target to improve the prognosis remain unknown. The expression of MSH6 at mRNA level indicated that MSH6 expressed higher in GBM tissues than that in normal ones. The transwell assay and expression levels of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) suggested that the capability of invasion and migration in U251-MSH6 was more stubborn. The intracranial tumor model was established with nude mice to further explore in vivo. The time-weight curve, overall survival, tumor volumes, expression levels of MMP-2 and MMP-9 in tissue, and hematoxylin and eosin staining all indicated that MSH6 had a positive effect on metastasis. The expression levels of related proteins suggested that the hypoxia TME induced by MSH6 may promote metastasis via epithelial to mesenchymal transition, stemness, and angiogenesis progress. MSH6 is an overexpressed oncogene in human GBM tissues, which accelerated metastasis by regulating hypoxia inducible factor-1A (HIF1A) to form a hypoxic TME in GBM. The MSH6 was a vital marker of GBM, making it a promising therapeutic target.