Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets.

Osteosarcoma (OS) has a high recurrence rate, disability rate, mortality and metastasis, it brings great economic burden and psychological pressure to patients, and then seriously affects the quality of life of patients. At present, the treatment methods of OS mainly include radiotherapy, chemotherapy, surgical therapy and neoadjuvant chemotherapy combined with limb salvage surgery. These treatment methods can relieve the clinical symptoms of patients to a certain extent, and also effectively reduce the disability rate, mortality and recurrence rate of OS patients. However, because metastasis of tumor cells leads to new complications, and OS cells become resistant with prolonged drug intervention, which reduces the sensitivity of OS cells to drugs, these treatments still have some limitations. More and more studies have shown that traditional Chinese medicine (TCM) has the characteristics of "multiple targets and multiple pathways," and can play an important role in the development of OS through several key signaling pathways, including PI3K/AKT, Wnt/ß-catenin, tyrosine kinase/transcription factor 3 (JAK/STAT3), Notch, transforming growth factor-ß (TGF-ß)/Smad, nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nuclear factor E2-related factor 2 (Nrf2), Hippo/YAP, OPG/RANK/RANKL, Hedgehog and so on. In this paper, the signaling pathways of cross-interference between active ingredients of TCM and OS were reviewed, and the development status of novel OS treatment was analyzed. The active ingredients in TCM can provide therapeutic benefits to patients by targeting the activity of signaling pathways. In addition, potential strategies for targeted therapy of OS by using ferroptosis were discussed. We hope to provide a unique insight for the in-depth research and clinical application of TCM in the fields of OS growth, metastasis and chemotherapy resistance by understanding the signaling crosstalk between active ingredients in TCM and OS.

Matrine restrains the development of colorectal cancer through regulating the AGRN/Wnt/ß-catenin pathway.

BACKGROUND: Colorectal cancer is a common malignant digestive tract tumor. This study aimed to explore the biological role and potential underlying mechanism of matrine in colorectal cancer. METHODS: The mRNA expression of AGRN was measured using RT-qPCR. Cell proliferation, migration, invasion and apoptosis were determined using CCK-8, EdU, transwell assays and flow cytometry, respectively. Xenograft tumor experiment was performed to explore the action of matrine and AGRN on tumor growth in colorectal cancer in vivo. Immunohistochemistry (IHC) assay was applied for AGRN, ß-catenin, and c-Myc expression in the tumor tissues from mice. RESULTS: Matrine dramatically repressed cell growth and reduced the level of AGRN in colorectal cancer cells. AGRN expression was boosted colorectal cancer tissues and cells. AGRN downregulation depressed cell proliferation, migration, invasion, and enhanced cell apoptosis in colorectal cancer cells. Moreover, matrine showed the anti-tumor effects on colorectal cancer cells via regulating AGRN expression. AGRN knockdown could inactivate the Wnt/ß-catenin pathway in colorectal cancer cells. We found that AGRN downregulation exhibited the inhibition action in the progression of colorectal cancer by modulating the Wnt/ß-catenin pathway. In addition, matrine could inhibit the activation of the Wnt/ß-catenin pathway through regulating AGRN in colorectal cancer cells. Furthermore, xenograft tumor experiment revealed that matrine treatment or AGRN knockdown repressed the development of colorectal cancer via the Wnt/ß-catenin pathway in vivo. CONCLUSION: Matrine retarded colorectal cancer development by modulating AGRN to inactivate the Wnt/ß-catenin pathway.

Nuclear receptor subfamily 3 group c member 2 (NR3C2) is downregulated due to hypermethylation and plays a tumor-suppressive role in colon cancer.

Nuclear receptor subfamily 3 group c member 2 (NR3C2) has been reported to function as a tumor suppressor in several tumors. However, the clinical significance and potential action mechanisms of NR3C2 in colon cancer (COAD) remain unclear. NR3C2 expression and its correlation with clinicopathological features in COAD were analyzed based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Receiver operating characteristic (ROC) curves and Human Protein Atlas (HPA) database were used to evaluate the diagnostic and prognostic values of NR3C2 in COAD. Immune infiltration and DNA methylation analyses were performed by Gene Set Cancer Analysis (GSCA) database. NR3C2-correlated genes were identified by UALCAN database and subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses. Cell apoptosis and proliferation were evaluated using TUNEL and CCK-8 assays, respectively. NR3C2 was downregulated in COAD based on TCGA and GEO databases, which may be due to promoter hypermethylation. NR3C2 expression was correlated with prognosis and immune infiltration of COAD. High NR3C2 expression displayed good diagnostic value in COAD. KEGG pathway analysis presented that NR3C2-correlated genes were mainly clustered in choline metabolism in cancer and apoptosis. In vitro experiments confirmed that NR3C2 overexpression induced apoptosis and suppressed proliferation in COAD cells. In conclusion, our study revealed the potential prognostic and diagnostic values of NR3C2 and provided insights into understanding the tumor-suppressive role of NR3C2 in COAD progression.

Tumor suppressor LHX6 upregulation contributes to the inhibitory effect of miR-346 knockdown on colorectal cancer cell growth.

Colorectal cancer (CRC) is one of the prevalent types of human malignancies and ranks as the second leading cause of cancer-associated death worldwide. Dysregulated miRNAs have been promulgated as oncogenes or tumor-suppressive genes participating in the initiation and progression of CRC. A recent study reported that miR-346 was highly expressed in CRC patients. However, the biological role and underlying mechanism of miR-346 in CRC remain elusive. qRT-PCR and western blot assays were employed to detect miR-346 and LIM homeobox domain 6 (LHX6) expression in CRC cells. Cell proliferation was evaluated by CCK-8 and BrdU assays. Apoptosis was evaluated by TUNEL assay. The interaction between miR-346 and LHX6 was assessed by luciferase reporter assay. Results showed that miR-346 expression was increased and LHX6 expression was reduced in CRC cells. miR-346 knockdown and LHX6 overexpression inhibited proliferation and promoted apoptosis of CRC cells. Additionally, we found that miR-346 negatively regulated LHX6 expression in CRC cells by directly targeting LHX6. LHX6 knockdown partially attenuated anti-miR-346-induced proliferation reduction and apoptosis promotion in CRC cells. Furthermore, miR-346 knockdown inhibited the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway in CRC cells by targeting LHX6. The present study indicated that miR-346 knockdown repressed cell growth in CRC cells by upregulating LHX6, and this was associated with inactivation of the Akt/mTOR pathway.