Extracellular matrix marker LAMC2 targets ZEB1 to promote TNBC malignancy via up-regulating CD44/STAT3 signaling pathway.

BACKGROUND: Triple negative breast cancer (TNBC) is a heterogeneous and aggressive disease characterized by a high risk of mortality and poor prognosis. It has been reported that Laminin γ2 (LAMC2) is highly expressed in a variety of tumors, and its high expression is correlated with cancer development and progression. However, the function and mechanism by which LAMC2 influences TNBC remain unclear. METHODS: Kaplan-Meier survival analysis and Immunohistochemical (IHC) staining were used to examine the expression level of LAMC2 in TNBC. Subsequently, cell viability assay, wound healing and transwell assay were performed to detect the function of LAMC2 in cell proliferation and migration. A xenograft mouse model was used to assess tumorigenic function of LAMC2 in vivo. Luciferase reporter assay and western blot were performed to unravel the underlying mechanism. RESULTS: In this study, we found that higher expression of LAMC2 significantly correlated with poor survival in the TNBC cohort. Functional characterization showed that LAMC2 promoted cell proliferation and migration capacity of TNBC cell lines via up-regulating CD44. Moreover, LAMC2 exerted oncogenic roles in TNBC through modulating the expression of epithelial-mesenchymal transition (EMT) markers. Luciferase reporter assay verified that LAMC2 targeted ZEB1 to promote its transcription. Interestingly, LAMC2 regulated cell migration in TNBC via STAT3 signaling pathway. CONCLUSION: LAMC2 targeted ZEB1 via activating CD44/STAT3 signaling pathway to promote TNBC proliferation and migration, suggesting that LAMC2 could be a potential therapeutic target in TNBC patients.

Notch signaling and targeted therapy in non-small cell lung cancer.

The Notch signaling pathway plays pivotal roles in cell proliferation, stemness and invasion of non-small cell lung cancer (NSCLC). The human Notch family consists of four receptors, namely Notch1, Notch2, Notch3, and Notch4. These receptors are transmembrane proteins that play crucial roles in various cellular processes. Notch1 mostly acts as a pro-carcinogenic factor in NSCLC but sometimes acts as a suppressor. Notch2 has been demonstrated to inhibit the growth and progression of NSCLC, whereas Notch3 facilitates these biological behaviors of NSCLC. The role of Notch4 in NSCLC has not been fully elucidated, but it is evident that Notch4 promotes tumor progression. At present, drugs targeting the Notch pathway are being explored for NSCLC therapy, a majority of which are already in the stage of preclinical research and clinical trials, with bright prospects in the clinical treatment of NSCLC.

Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway.

Multiple myeloma (MM) is a malignant plasma cell disease. The activity of PIK3CG (PI3K catalytic subunit γ) is regulated directly by G-protein-coupled receptor and has been confirmed to be highly expressed in MM cells. This study aimed to determine the effect of pharmacological inhibition of PIK3CG on MM. We found that different concentrations of the PIK3CG inhibitor AS-605240 could suppress the growth of MM cell lines and the expression of c-Myc. The combination of PIK3CG inhibitor and the chemotherapy Melphalan could effectively inhibit the proliferation and migration of MM cells, promote the cell apoptosis, and decrease the ratio of Bcl-2/Bax and the expression of vimentin. The expression of proto-oncogene c-Myc was decreased and the sensitivity of cells to chemotherapeutic drugs was enhanced. Collectively, PIK3CG regulates growth of MM via c-Myc pathway, thus emerging as a promising molecular targeted therapy.

Characterization of a germline variant TNS1 c.2999-1G > C in a hereditary cancer syndrome family.

Hereditary cancer syndromes result from the presence of inherited pathogenic variants within susceptibility genes. However, the susceptibility genes associated with hereditary cancer syndrome remain predominantly unidentified. Here, we reported a case of hereditary cancer syndrome observed in a Chinese family harboring a germline mutation in Tensin1 (TNS1). We described a 59-year-old female patient presented with Multiple myeloma and Thyroid carcinoma. The proband and her family members exhibited suspected tumor syndrome due to occurrences of other cancer cases. After oncogenetic counseling, whole-exome sequencing and Sanger sequencing were conducted and a primary driver mutation of TNS1 (NM_022648.7:c.2999-1G > C) was detected. Gene Expression Profiling Interactive Analysis revealed that TNS1 was expressed lower in different tumors when compared to normal, including Pancreatic adenocarcinoma, Breast invasive carcinoma, Thyroid carcinoma andColon adenocarcinoma cells. Despite the well-established role of TNS1 as a tumor suppressor in breast cancer and colorectal cancer, its potential utility as a marker gene for diagnosis and treatment of pancreatic cancer remains uncertain. Here, our data demonstrated that knockdown of TNS1 could promote cell proliferation and migration in Pancreatic adenocarcinoma (PDAC) cells. In addition, TNS1 regulated migration through EMT signaling pathway in PDAC cells. Our findings proposed that this variant was likely involved in cancer predisposition by disrupting the normal splicing process. In summary, we presented a genetic disease by linking an intronic mutation inTNS1. We aim to provide early detection of cancers by identifying germline variants in susceptibility genes.

Targeting C21orf58 is a Novel Treatment Strategy of Hepatocellular Carcinoma by Disrupting the Formation of JAK2/C21orf58/STAT3 Complex.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Functionally uncharacterized genes are an attractive repository to explore candidate oncogenes. It is demonstrated that C21orf58 displays an oncogenic role in promoting cell growth, tumorigenesis and sorafenib resistance of HCC cells by abnormal activation of STAT3 signaling. Mechanistically, a novel manner to regulate STAT3 signaling that adaptor C21orf58 forms a ternary complex is reveal with N-terminal domain of STAT3 and SH2 domain of JAK2, by which C21orf58 overactivates wild-type STAT3 by facilitating its phosphorylation mediated by JAK2, and hyper-activates of constitutively mutated STAT3 due to preferred binding with C21orf58 and JAK2. Moreover, it is validated that inhibition of C21orf58 with drug alminoprofen, selected by virtual screening, could effectively repress the viability and tumorigenesis of HCC cells. Therefore, it is identified that C21orf58 functions as an oncogenic adaptor, reveal a novel regulatory mechanism of JAK2/STAT3 signaling, explain the cause of abnormal activity of activated mutants of STAT3, and explore the attractive therapeutic potential by targeting C21orf58 in HCC.