Relationship of up-regulation of 67-kd laminin receptor to grade of cervical intraepithelial neoplasia and to high-risk HPV types and prognosis in cervical cancer

Objective To evaluate the 67-kd laminin receptor (67LR) in cervical cancer and its molecular links to oncogenic HPV types. Study Design As pan of the HPV-PathogenISS Study, a series of 150 squamous cell carcinomas (SCCs) and 152 carcinoma in situ (CIN lesions were examined using immunohistochemical staining for LR67 and tested for LR67 using polymerase chain reaction (PCR) with 3 primer sets (MY09/11, GP5(+)/GP6(+), SPF). Followup data were available for all SCC patients, and 67 CIN lesions had been monitored with serial PCR for HPV clearance/persistence after cone treatment. Results 67LR expression increased in parallel with increasing grade of CIN (p = 0.0001), with the most dramatic up-regulation upon the transition from CIN 2 to CIN 3 and further to SCC. This increased expression was associated with CIN 3/cancer at OR 17.04 (95% CI 7.28-39.87). The seemingly significant association of 67LR with high-risk HPV (HR-HPV) detection (OR 2.20, 95% CI 1.27-3.80) was due to confounding by the histologic grade (Mantel-Haenszel common OR=1.118, 95% CI 0.576-2.168). Using performance indicators, 67LR expression was of little value as a marker of HR-HPV type, and it did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, 67LR expression was not an independent prognostic factor in cervical cancer. Conclusion In cervical carcinogenesis, both integrin- and nonintegrin-type LRs (67LR) probably have functions complementary to each other, mediating transient early and stable adhesions, respectively. Up-regulated 67LR expression is significantly associated with progression from CIN 2 to CIN 3 as a marker of cell proliferation. 67LR is probably orchestrated by mechanisms independent of HR-HPV oncoproteins, which seem to be more closely associated with integrin-type laminin receptors.