The CaSm (LSm1) oncogene promotes transformation, chemoresistance and metastasis of pancreatic cancer cells

Abstract

The cancer-associated Sm-like (CaSm) oncogene is overexpressed in 87% of human pancreatic tumor samples and CaSm knockdown has demonstrated therapeutic efficacy in murine models of pancreatic cancer. Evidence indicates that CaSm modulates messenger RNA degradation; however, its target genes and the mechanisms by which CaSm promotes pancreatic cancer remain largely unknown. Here, we demonstrate that the CaSm overexpression alters several hallmarks of cancer—including transformation, proliferation, chemoresistance and metastasis. Doxycycline-induced CaSm expression enhanced proliferation and both anchorage-dependent and -independent growth of the human Panc-1 cells in vitro. CaSm induction decreased gemcitabine-induced cytotoxicity and altered the expression of apoptotic regulation genes, including Bad, E2F1 and Bcl-XL. CaSm-overexpressing Panc-1 cells were twofold more migratory and fourfold more invasive than the driver controls and demonstrated characteristics of epithelial-to-mesenchymal transition such as morphological changes and decreased E-cadherin expression. CaSm induction resulted in changes in RNA expression of metastasis-associated genes such as MMP1, SerpinB5, uPAR and Slug. Using a murine model of metastatic pancreatic cancer, injection of CaSm-induced Panc-1 cells resulted in a higher abundance of hepatic metastatic lesions. Overall, CaSm overexpression contributed to a more aggressive cancer phenotype in Panc-1 cells, further supporting the use of CaSm as a therapeutic target against pancreatic cancer.

Cancer- and behavior-related genes are targeted by selection in the Tasmanian devil (Sarcophilus harrisii)

“…Other candidates, such as PRRX2 and CST3, confer metastatic properties to cancer cells through the TGF-β pathway [ 34 , 35 ]. Similarly, FOXN3 [ 36 ], HMGCS2 [ 37 ], LSM1 [ 38 ], PHGDH [ 39 ], RIN2 [ 40 ], TRPM8[ 41 ], are known regulators of metastatic processes. In total, over 30 selection candidates identified in this study are known to participate in metastasis-related mechanisms.…”

Potential Therapeutic and Prognostic Values of LSM Family Genes in Breast Cancer

“…It was previously determined that LSM1, an oncogene when working in combination with BAG4 and C8orf4, can influence growth factors and affect phenotypes in human mammary epithelial cells [80,81]. Additionally, higher expression of LSM1 resulted in a higher abundance of hepatic metastatic lesions, due to previous report [82]. Consistently, LSM1 has been found as an oncogene activated by gene amplification and it could play a crucial role in breast cancer development and progression [23].…”

Prognostic value and potential molecular mechanism of the like-Sm gene family in early-stage pancreatic ductal adenocarcinoma

“…PDAC is related to the oncogene K-ras, and downregulation of p53, p16/CDK2, and DPC4 (9). LSM genes are significantly more highly expressed in pancreatic cancer than in surrounding normal tissues (11). LSM proteins are ubiquitous in eukaryotes, where they are present in both the nucleus and cytoplasm, and characterized by the Sm domain.…”

“…There are 14 genes in the like-sm ( LSM ) gene family; in animals, LSMs generally exist in the form of heptameric complexes, including the LSM1-7 and LSM2-8 complexes, and they are closely related to splicing and cytoplasmic mRNA degradation ( 10 ). LSM genes were significantly overexpressed in pancreatic cancer compared with surrounding normal tissues, and they act as oncogenes promoting cancer transformation, proliferation, resistance, and metastasis ( 11 ). The mechanism by which LSM genes promote PDAC transformation remains unclear.…”