No abstract

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy that shows high cancer-mortality and poor prognosis, in the absence of obvious symptoms and biomarkers for early diagnosis. Gemcitabine is a type of chemotherapy drug which commonly used to treat PDAC, however, the rapid acquisition of resistance to gemcitabine treatment has been observed in many of PDAC patients. The miRNA-producing enzymes Dicer is crucial for the maturation of miRNAs, and we found previously that ERK/Sp1 signaling transactivate both gene and protein expressions of Dicer, leading an acquisition of gemcitabine resistance in pancreatic cancer cells both in vitro and in vivo. In this study, we further identified that phosphomimetic S1016E of Dicer may regulate miRNAs maturation, resulting an imbalance of glutaminase (GLS) and glutamine synthetase (GS/GLUL). Metabolism analysis revealed that gemcitabine-resistant PANC-1 (PANC-1/GEM) cells have high glutamine dependence and GLS/GLUL ratio. Our study suggests that phosphomimetic Dicer S1016E plays a critical role in glutamine metabolism reprogramming and gemcitabine resistance of pancreatic cancer. Citation Format: Ching-Feng Chiu, Ji Min Park, Yu-Shiuan Shen, Chia-Ying Lin, Tung-Wei Hsu, Yen-Hao Su, Hsin-An Chen. Phosphomimetic Dicer rewires glutamine metabolism and gemcitabine resistance in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6386.

Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing–related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown–induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.