APOA5 alleviates reactive oxygen species to promote oxaliplatin resistance in PIK3CA-mutated colorectal cancer.

Although platinum-based chemotherapy is the frontline regimen for colorectal cancer (CRC), drug resistance remains a major challenge affecting its therapeutic efficiency. However, there is limited research on the correlation between chemotherapy resistance and lipid metabolism, including PIK3CA mutant tumors. In this present study, we found that PIK3CA-E545K mutation attenuated cell apoptosis and increased the cell viability of CRC with L-OHP treatment in vitro and in vivo. Mechanistically, PIK3CA-E545K mutation promoted the nuclear accumulation of SREBP1, which promoted the transcription of Apolipoprotein A5 (APOA5). APOA5 activated the PPARγ signaling pathway to alleviate reactive oxygen species (ROS) production following L-OHP treatment, which contributed to cell survival of CRC cells. Moreover, APOA5 overexpression enhanced the stemness-related traits of CRC cells. Increased APOA5 expression was associated with PIK3CA mutation in tumor specimens and poor response to first-line chemotherapy, which was an independent detrimental factor for chemotherapy sensitivity in CRC patients. Taken together, this study indicated that PIK3CA-E545K mutation promoted L-OHP resistance by upregulating APOA5 transcription in CRC, which could be a potent target for improving L-OHP chemotherapeutic efficiency. Our study shed light to improve chemotherapy sensitivity through nutrient management in CRC.

GLTP Is a Potential Prognostic Biomarker and Correlates with Immunotherapy Efficacy in Cervical Cancer.

Cervical cancer (CC) is the fourth most commonly diagnosed cancer in women worldwide. The prognosis of CC patients remains poor. The objective of our study was to explore the potential of glycolipid transfer protein (GLTP) in predicting the prognosis of CC and patients' response to immunotherapy. The expression of GLTP was determined using TCGA and GEO datasets. The prognostic value of GLTP in CC patients was analyzed using Kaplan-Meier analysis and multivariate analysis. The relationships between BTBD10 and immunological checkpoints, immune checkpoint genes, and ferroptosis-related genes were analyzed to explore the impact of GLTP on CC immunotherapy. According to the dysregulated expressions of BTBD10, the IC50 distribution of various targeted medicines was studied. In this study, we found that GLTP expression was distinctly upregulated in CC specimens. However, Kaplan-Meier assays showed that CC patients with low GLTP expressions tended to exhibit a shorter overall survival. Importantly, multivariate assays revealed that GLTP expression was an independent prognostic factor for CC patients. Moreover, we observed that GLTP expression was related to CD4+ T cells, macrophages, and dendritic cells (DCs). Meanwhile, GLTP expressions were associated with those of immune checkpoints, ferroptosis-related genes, and m6A-related genes. The IC50 of Cisplatin, Docetaxel, and Paclitaxel was lower in the high-GLTP-expressing group. Taken together, GLTP was expected to be a prognostic and immunotherapeutic marker for CC.

LncRNA OSER1-AS1 interacts with miR-612/FOXM1 axis to modulate gefitinib resistance of lung adenocarcinoma.

Long noncoding RNAs (lncRNAs) play crucial roles in the acquired resistance to EGFR-directed therapies in lung cancer. LncRNA OSER1-AS1 has been reported to promote tumorigenesis of hepatocellular carcinoma. However, its functions and underlying molecular mechanisms remain unclear in the acquired gefitinib-resistance of lung cancer. Our study revealed that increased expression of OSER1-AS1 was correlated with gefitinib resistance in lung adenocarcinoma. Higher OSER1-AS1 expression predicted disease progression of lung adenocarcinoma patients. The in vitro assays indicated OSER1-AS1 contributed to gefitinib resistance of lung adenocarcinoma cells via inhibiting cell apoptosis and cell cycle arrest. In vivo experiments showed that the knockdown of OSER1-AS1 restored the sensitivity of lung cancer cells to gefitinib. Further studies showed that OSER1-AS1 functioned as a molecular sponge of miR-612. OSER1-AS1 down-regulated miR-612 to increase FOXM1 expression, suggesting that miR-612/FOXM1 axis was regulated by OSER1-AS1, which was partially responsible for gefitinib resistance of lung adenocarcinoma. In conclusion, OSER1-AS1 promoted gefitinib resistance of lung adenocarcinoma through the miR-612/FOXM1 axis.

Ligustrazine reverts anthracycline chemotherapy resistance of human breast cancer by inhibiting JAK2/STAT3 signaling and decreasing fibrinogen gamma chain (FGG) expression.

Chemotherapy resistance is a major challenge for breast cancer treatment. It is necessary to elucidate the mechanisms of anthracycline resistance to develop new chemosensitizers for breast cancer. In this study, we explored the effects of ligustrazine (TMP) on reverting anthracycline resistance of breast cancer cells, as well as its related mechanisms. Clinical significance of fibrinogen gamma chain (FGG) expression was also analyzed in breast cancer tissues. We provided evidence that breast tumor cell derived FGG participated in anthracycline chemoresistance of breast cancer. Further, TMP reverted epirubicin resistance by inhibiting JAK2/STAT3 signaling and decreasing FGG expression. Meanwhile, the elimination of cancer stem cell was observed in TMP treated chemoresistant breast cancer cells. Clinical analysis demonstrated that patients with FGG expressing breast cancer showed a dramatically low response to anthracycline-based chemotherapy and poor survival. Our data collectively indicated that FGG was an independent detrimental factor for anthracycline based chemotherapy for breast cancer patients. TMP was a novel chemosensitizer for FGG-induced anthracycline chemoresistance in breast cancer treatment.

Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer.

Pemetrexed is a candidate chemotherapy regimen for anthracycline- and taxane-pretreated advanced breast cancer. However, to the best of our knowledge, no efficient treatment efficacy biomarkers have been identified. In the present study, the potential correlation between thymidylate synthase (TYMS) expression and clinical response to pemetrexed was examined in advanced breast cancer. A retrospective collection was performed by using 77 advanced breast cancer subjects, who received at least three cycles of pemetrexed treatment in the Second Hospital of Shandong University hospital. TYMS expression was detected using immunohistopathological staining. The correlations between TYMS and therapeutic efficacies of different chemotherapy treatment were analyzed. The objective response rate (ORR) and disease control was 31.17 and 64.94%, respectively. Immunohistochemical staining demonstrated that TYMS expression was observed in the cytoplasm and nuclei of breast cancer cells. High TYMS expression was observed in 32 specimens. Elevated TYMS expression was correlated with higher histological grade and lymph node metastasis (P<0.05). Furthermore, significantly higher TYMS expression was observed in treatment-resistant patients than response ones (P<0.05). Patients with low expression level of TYMS exhibit significantly higher ORR. Cox regression analysis indicated that elevated TYMS expression was a detrimental factor for pemetrexed treatment for advanced breast cancer patients. The present results suggested that TYMS expression levels predicts therapeutic sensitivity of pemetrexed chemotherapy in advanced breast cancer, indicating that it may be a useful biomarker to choose chemotherapy regimens.

PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer.

Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5+ CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA mutation/LGR5+ expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA mutation/LGR5+ expression was a potential biomarker for monitoring chemotherapy resistance in CRC.

(-)-Epigallocatechin-3-gallate inhibits nasopharyngeal cancer stem cell self-renewal and migration and reverses the epithelial-mesenchymal transition via NF-κB p65 inactivation.

The cancer stem cell (CSC) theory states that many types of cancer, including nasopharyngeal cancer (NPC), are initiated from and maintained by CSCs, which may be responsible for tumor relapse and resistance to therapy. It is imperative that nasopharyngeal cancer stem cells (NPCSCs) be specifically targeted to eradicate NPC and prevent recurrence. Epigallocatechin-3-gallate (EGCG) inhibits cancer progression by attenuating NF-κB p65 activity, which is upregulated in CSCs and plays an important role in epithelial-mesenchymal transition (EMT). The purpose of this study is to confirm the self-renewal and migration inhibitory effects of EGCG toward NPCSCs and to clarify its mechanism of activity. We enriched and characterized NPCSCs by collecting spheroid-derived cells grown in serum-free medium (SFM) and examined the effects of EGCG on the characteristics of NPCSCs and studied the underlying mechanisms using soft agar colony assays, transwell migration assays, reverse transcriptase polymerase chain reaction (RT-PCR), Western blot analysis, immunofluorescence staining, and xenograft studies. NPC spheroids enriched from NPC cell lines acquired CSC traits and underwent EMT. EGCG inhibited the NPCSCs' self-renewal and migration and reversed EMT, and combined treatment with EGCG and cisplatin reduced the growth of CSC tumor xenografts. Moreover, EGCG inhibited NF-κB p65 activity by modulating the cellular localization of p65 and decreasing the transcriptional regulation of NF-κB p65 on Twist1 expression. NF-κB p65 is a novel therapeutic target in NPCSCs, and the inhibition of activated NF-κB p65 in CSCs by EGCG may offer an effective treatment for NPC.