Genomic gain of the PRL-3 gene may represent poor prognosis of primary colorectal cancer, and associate with liver metastasis

Abstract

PRL-3 genomic copy number is increased in colorectal cancer (CRC), and PRL-3 expression is closely associated with lymph node and liver metastasis of CRC. However, the clinical significance of PRL-3 genomic gain for CRC remains obscure. Here, PRL-3 genomic status in 109 primary CRC tumors and in 44 CRC tumors that had metastasized to the liver, was quantified using real time PCR. Association of PRL-3 genomic status with clinicopathological factors and prognosis was assessed in detail. PRL-3 genomic gain was identified in 31 primary CRC (27.4 %) and was more frequently seen in stage III than in stage II (p = 0.025). Among the clinicopathological factors assessed, PRL-3 genomic gain was significantly associated with poorly differentiated histology (p = 0.0039). Moreover, CRC patients with PRL-3 genomic gain exhibited poorer prognosis than those with no gain in stage II-IV CRC (p = 0.017). PRL-3 genomic gain was identified in 18 (41 %) of the liver metastasis tumors, and this frequency of gain was significantly increased as compared to that of the corresponding primary CRCs (11 %) (p = 0.001). Our findings suggested that PRL-3 genomic gain may represent an aggressive phenotype of primary CRC, and may associate with liver metastasis.

Critical relevance of genomic gains of PRL‑3/EGFR/c‑myc pathway genes in liver metastasis of colorectal cancer

“…PRL-3 is a member of the protein tyrosine phosphatase family, the members of which play important roles in signalling pathways. We recently reported that PRL-3 genomic amplification and overexpression were confirmed in gastric cancer, oesophageal squamous cell cancer, and CRC (23)(24)(25)(26), and we revealed a relationship between these changes and cancer invasion and a poor prognosis. Especially in terms of CRC, PRL-3 genomic gains (defined larger as over two-fold) were significantly increased in liver metastases (26).…”

“…The genomic gain statuses of c-myc and EGFR were then compared with the PRL-3 genomic gain status in the 35 previously reported primary CRC and corresponding liver metastases (Fig. 1C) (26). In the primary CRC tumours, genomic gains in PRL-3, c-myc, and EGFR were seen in 4 (11%), 4 (11%), and 13 (37%) cases, respectively.…”

“…Gene copy number changes are major aberrations that occur mostly upstream of cancer cells, and their potential role as molecular targets in cancer therapy has been reported (27). Nakayama et al (26) showed, for the first time, that a genomic gain in PRL-3 is associated with lymph node metastasis and liver metastasis in CRC. In the current study, Q-PCR analyses for the c-myc gene and the EGFR gene were additionally performed using both liver metastases and the corresponding primary tumours, and the results were compared with the genomic gain status of PRL-3 to investigate the relationship among the 3 genes during liver metastasis from CRC.…”

“…A total of 35 patients with histologically confirmed liver metastases (synchronous, n=11 and metachronous, n=24) of CRC underwent surgical resection of the liver and primary tumours at the Department of Surgery, Kitasato University School of Medicine (Sagamihara, Japan), between 1993 and 2007. Nakayama et al previously reported 44 cases in this series (26), but 9 of those cases were excluded because additional exploration was impossible due to a lack of available DNA from the tumour tissues. The 35 cases in the present series were composed of stage I (n=3), stage IIA (n=7), stage IIB (n=1), stage IIIB (n=9), stage IIIC (n=2), stage IVA (n=9), and stage IVB (n=4) disease at the time of the diagnosis of the primary CRC.…”

Physiological and oncogenic roles of the PRL phosphatases

“…Interestingly, this PTP was undetectable in normal colorectal epithelia, but was expressed at low levels in primary tumors, indicating a possible oncogenic role for this phosphatase during cancer progression. Since this pioneering study, many research groups have corroborated this finding in colorectal cancer not only for PRL-3 [67][68][69][70][71][72][73][74][75] but also for the other two PRLs [76]. In most of these studies, high expression of PRL-3 correlates with poor survival, indicating that this PTP is a promising biomarker not only for early stages of colorectal cancer but also for colon metastases.…”