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

E C Little,P M Watson,C Wang,D K Watson,D J Cole,E R Camp

doi:10.1038/oncsis.2015.45

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.

Highlights

Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer-related deaths in the nation
Induction of cancer-associated Sm-like oncogene (CaSm) levels in human Panc-1 cells differences were even more pronounced at lower plating densities of 50 cells per well, where CaSm-induced cells produced four times the number of colonies (42 ± 8.7 compared with 11 ± 4; CaSm protein expression was evaluated via western blot analysis Figure 1d), indicating that CaSm produced a transformed cellular in a panel of human PC cell lines to identify a cell line with lower phenotype with less dependence on cellular density and cytokine levels of basal expression
CaSm induction enhanced cellular migration and invasion and metastatic gene expression As PC is regularly diagnosed at advanced clinical stages, with over 50% of patients presenting with metastatic disease,[1] we evaluated whether CaSm overexpression, which is believed to occur early in neoplastic progression, contributes to cellular migration and invasion

Summary

Introduction

Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer-related deaths in the nation. Comparing absorbance to their respective untreated controls, the tet-on driver Panc-1 cells demonstrated 26.5% survival after treatment with 100 μM gemcitabine the tet-on CaSm cells maintained 88.3% viability at this concentration (Figure 2c).

Results

Conclusion