FAK x PXN

Poorly cohesive gastric carcinoma, particularly signet-ring cell (SRC) carcinoma, is an aggressive gastric cancer (GC) subtype with high metastatic potential and poor prognosis. Sialylation plays a critical role in tumor progression, but its functional significance in SRC malignancy and microenvironmental regulation remains unclear. This study investigated ST6Gal-Ⅰ's mechanistic contributions to SRC aggressiveness, focusing on epithelial-mesenchymal transition (EMT), stromal interactions, and metastatic signaling.

Multiple SRC and non-SRC GC cell lines, patient-derived organoids, and stromal cells (MSCs, HUVECs) were utilized. Techniques included co-culture models (transwell and direct contact), immunohistochemistry, western blotting, functional assays (transwell migration, wound healing, sphere/colony formation, EdU proliferation), and lectin staining. ST6Gal-Ⅰ expression was modulated via shRNA knockdown or overexpression. Mechanistic analyses focused on integrin-β1 (ITGβ1)/FAK/Paxillin signaling and stromal reprogramming. Statistical significance was determined using ANOVA with post hoc tests.

ST6Gal-Ⅰ exhibited microenvironment-dependent regulation: low in vitro expression in SRC cells was rescued by stromal co-culture or extracellular matrix (ECM) contact, mirroring high in vivo expression. ST6Gal-Ⅰ overexpression promoted EMT, stemness, angiogenesis, and proliferation. It facilitated MSCs differentiation into cancer-associated fibroblasts (CAFs) via α-SMA/FAP upregulation. Mechanistically, ST6Gal-Ⅰ activated the ITGβ1/FAK/Paxillin axis to enhance cell-ECM adhesion. Silencing ST6Gal-Ⅰ reversed these phenotypes, suppressing malignancy and stromal crosstalk.

ST6Gal-Ⅰ is a microenvironment-sensitive driver of SRC progression, orchestrating EMT, stemness, angiogenesis, and stromal reprogramming through ITGβ1/FAK/Paxillin signaling. Its dual role in tumor-autonomous behaviors and stromal co-option highlights its potential as a therapeutic target. Targeting ST6Gal-Ⅰ or downstream effectors (e.g., FAK, CAF-derived signals) may disrupt SRC metastasis and improve clinical outcomes.

Nesfatin-1, initially identified as an appetite-regulating hormone, has also been detected in various cancer tissues and implicated in tumorigenesis. However, its role in the proliferation and migration of lung cancer cells remains unclear. This study aims to investigate the effects of nesfatin-1 on the proliferation and migration of human lung cancer cells and elucidate the underlying molecular mechanisms. The expression of nesfatin-1 protein and NUCB2 mRNA was detected in the immortalized normal human bronchial cell line BEAS-2B and the non-small-cell lung cancer cell line H1299. Immunohistochemical staining revealed the localization of nesfatin-1 binding sites in both cell lines. Nesfatin-1 treatment significantly increased the proliferation and migration of BEAS-2B cells but not of H1299 cells. The expression levels of cell proliferation-related genes, such as TGFα, PXN, MTOR, and CCND1, were upregulated in BEAS-2B cells, with no significant changes observed in H1299 cells. In addition, phosphorylation of FAK, PI3 K, and AKT was increased in BEAS-2B cells, whereas only FAK phosphorylation was increased in H1299 cells. To further assess the role of endogenous nesfatin-1, NUCB2 expression was silenced using small interfering RNA. Knockdown of NUCB2 suppressed proliferation and migration of BEAS-2B cells, as well as their expression of TGFα, PXN, MTOR, and CCND1; however, it had no significant effect on H1299 cells. These results suggest that nesfatin-1 promotes proliferation and migration in normal lung epithelial cells but not in lung cancer cells. Further research is needed to elucidate the molecular mechanisms underlying the differential effects of nesfatin-1 on normal and cancerous lung cells.

During heart disease, the cardiac extracellular matrix (ECM) undergoes a structural and mechanical transformation. Cardiomyocytes sense the mechanical properties of their environment, leading to phenotypic remodeling. A critical component of the ECM mechanosensing machinery, including the protein talin, is organized at the cardiomyocyte costamere. Our previous work indicated a different talin tension, depending on the ECM stiffness, but the effects on downstream signaling remained elusive. Here, we identify that the talin interacting proteins DLC1 (deleted in liver cancer 1), RIAM (Rap1-interacting adaptor molecule), and paxillin each preferentially bind to talin at a specific ECM stiffness, this interaction is preserved in the absence of tension, and the interaction is regulated through focal adhesion kinase signaling. Moreover, DLC1 regulates cardiomyocyte RhoA activity in a stiffness-dependent way, whereby the loss of DLC1 results in myofibrillar disarray. Together, this study demonstrates a mechanism of imprinting mechanical information into the talin interactome to fine-tune RhoA activity, with impacts on cardiac health and disease.