High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer

Abstract

Pancreatic cancer has an extremely poor prognosis, and identification of novel predictors of therapeutic efficacy and prognosis is urgently needed. Chemoresistance-related molecules are correlated with poor prognosis and may be effective targets for cancer treatment. Here, we aimed to identify novel molecules correlated with chemoresistance and poor prognosis in pancreatic cancer. We established 10 patient-derived xenograft (PDX) lines from patients with pancreatic cancer and performed next-generation sequencing (NGS) of tumor tissues from PDXs after treatment with standard drugs. We established a gene-transferred tumor cell line to express chemoresistance-related molecules and analyzed the chemoresistance of the established cell line against standard drugs. Finally, we performed immunohistochemical (IHC) analysis of chemoresistance-related molecules using 80 pancreatic cancer tissues. From NGS analysis, we identified olfactomedin-4 (OLFM4) as having high expression in the PDX group treated with anticancer drugs. In IHC analysis, OLFM4 expression was also high in PDXs administered anticancer drugs compared with that in untreated PDXs. Chemoresistance was observed by in vitro analysis of tumor cell lines with forced expression of OLFM4. In an assessment of tissue specimens from 80 patients with pancreatic cancer, Kaplan-Meier analysis showed that patients in the low OLFM4 expression group had a better survival rate than patients in the high OLFM4 expression group. Additionally, multivariate analysis showed that high expression of OLFM4 was an independent prognostic factor

High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer

“…The establishment of the PDX model has been previously described by the authors ( 34 ). A total of 1,204 NSG mice were obtained from the Jackson Laboratory.…”

“…Immunohisto-chemistry (IHC) and gene analysis were conducted to confirm whether PDXs retained the histological and genetic characteristics of the original patient tissues even following repeated passaging. For the methodology in this section, the same procedures we used as described in a previous study by the authors ( 34 ).…”

“…PDXs from pancreatic cancer. Anticancer drugs (GEM as monotherapy or GEM and nab-paclitaxel as combination therapy) or saline as an untreated control were intraperitoneally injected into the PDXs as described in a previous study by the authors (34). In brief, chemotherapeutic drugs or saline were administered to the PDX models by an intra-abdominal injection on days 1, 4 and 7; no injection was performed on day 10.…”

“…Transcriptome analysis. For the methodology for transcriptome analysis, the same methods and procedures were used as previously described (34). Paired-end reads were mapped to all or any human RefSeq transcripts (hg38 coordinates) and mouse RefSeq transcripts (mm 10 coordinates) by bowtie 1.1.2 (37), with one mismatch at most.…”

“…The present study comprised a successive cohort of 80 patients with histopathologically-confirmed pancreatic cancer who had undergone surgical excision at the Showa University Hospital), from January 1, 2008 to December 31, 2017. The patient cohort of the present study is identical to that of a previous study by the authors (34). The study protocol was approved by the Ethics Committee of the Showa University School of Medicine (approval no.…”