LIMS1 Promotes Pancreatic Cancer Cell Survival under Oxygen–Glucose Deprivation Conditions by Enhancing HIF1A Protein Translation

Abstract

Purpose: Oxygen and glucose deprivation is a common feature of the solid tumor. Regulatory network underlying the adaptation of cancer cells to the harsh microenvironment remains unclear. We determined the mechanistic role of LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) in cancer cell survival under oxygen-glucose deprivation conditions. Experimental Design: The expression level of LIMS1 was determined by IHC staining and analyzing the mRNA expression profiles from The Cancer Genome Atlas of three human solid tumors. Roles of LIMS1 in cancer cell metabolism and growth were determined by molecular and cell biology methods. A jetPEI nanocarrier was used as the vehicle for anti-LIMS1 siRNAs in mouse models of cancer therapeutics.Results: LIMS1 expression was drastically elevated in pancreatic ductal adenocarcinoma (PDAC). High LIMS1 level was associated with advanced TNM stage and poor prognosis of patients with tumor. Increased LIMS1 expres-sion was pivotal for tumor cells to survive in the oxygenglucose deprivation conditions. Mechanistically, LIMS1 enhanced GLUT1 expression and membrane translocation, which facilitated tumor cell adaptation to the glucose deprivation stress. Furthermore, LIMS1 promoted HIF1A protein translation by activating AKT/mTOR signaling, while hypoxia-inducible factor 1 (HIF1) transactivated LIMS1 transcription, thus forming a positive feedback loop in PDAC cell adaptation to oxygen deprivation stress. Inhibition of LIMS1 with jetPEI nanocarrier-delivered anti-LIMS1 siRNAs significantly increased cell death and suppressed tumor growth.Conclusions: LIMS1 promotes pancreatic cancer cell survival under oxygen-glucose deprivation conditions by activating AKT/mTOR signaling and enhancing HIF1A protein translation. LIMS1 is crucial for tumor adaptation to oxygenglucose deprivation conditions and is a promising therapeutic target for cancer treatment. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

A nicotine-induced positive feedback loop between HIF1A and YAP1 contributes to epithelial-to-mesenchymal transition in pancreatic ductal adenocarcinoma

“…Upregulation of HIF1A protein in tumor tissues can be achieved by promoting DNA transcription, enhancing mRNA translation, or inhibiting proteasomal degradation [34]. The upregulation or knockdown of YAP1 did not change the mRNA level of HIF1A in the absence or presence of nicotine ( Fig.…”

SWATH-MS based proteomic profiling of pancreatic ductal adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways

“…Additionally, ACTN1 has been identified as a key regulator of PDAC progression, using a multidimensional systems-level analysis approach [46]. Increased LIMS1 (LIM and senescent cell antigen-like-containing domain protein 1), a focal adhesion protein, has been associated with poor prognosis in laryngeal and pancreatic cancers [47,48]. Also, during the knockdown of LIMS1, apoptosis was induced in breast cancer cells [49].…”

“…Also, during the knockdown of LIMS1, apoptosis was induced in breast cancer cells [49]. In PDAC, it was found to promote cell survival under hypoxic conditions by activating the AKT/mTOR signalling pathway [47]. ILK (Integrin-linked kinase) which interacts with LIMS1 [50] was also overexpressed in PDAC tumours.…”

Sciellin stimulates gallbladder cancer proliferation and tumor-association thrombosis via formation of neutrophil extracellular traps

“…Five random fields (20× magnification) were evaluated using a light microscope. The final scores were determined by multiplying the scores of the intensity with those of the extent and dividing the samples into four grades: 0, negative (-); 1-2, low staining (+); 3-5, medium staining (++); 6-9, high staining (+++) (15) (16).Immunofluorescence staining was performed to detect the neutrophils. In brief, NETs were added on 13-mm glass coverslips (Fisher Scientific) and allowed to adhere overnight at 4℃on coverslips followed by culture in the presence of anti-citH3(1:100 NOVUS, USA) and NE (1:100, NOVUS) antibody at 4°C over night.…”