Department of Biology, Clarkson University, Potsdam, NY, United States of America.
Department of Mathematics, Clarkson University, Potsdam, NY, United States of America.
Sci Rep. 2018 Oct 18;8(1):15402. doi: 10.1038/s41598-018-33865-2.
A major risk factor for cervical cancer is persistent infection with high-risk human papillomaviruses (HPV) which can cause cervical intraepithelial neoplasia. Greater than 90% of cervical cancers develop in the transformation zone (TZ), a small region of metaplastic squamous epithelium at the squamocolumnar junction between endocervix and ectocervix. However, it is unclear why this region is highly susceptible to malignant progression. We hypothesized that cells from TZ were more susceptible to dysplastic differentiation, a precursor to cervical cancer. We used three-dimensional organotypic culture to compare differentiation of HPV16-immortalized epithelial cell lines derived from ectocervix, TZ, and endocervix. We show that immortal cells from TZ or endocervix form epithelia that are more dysplastic than immortal cells from ectocervix. A higher percentage of immortal cells from TZ and endocervix express the proliferation marker Ki-67 and are positive for phospho-Akt. Immortal cells from TZ and endocervix invade collagen rafts and express increased levels of matrix metalloproteinase-1. Inhibition of MMP-1 or Akt activity blocks invasion. We conclude that HPV16-immortalized cells cultured from TZ or endocervix are more susceptible to dysplastic differentiation, and this might enhance their susceptibility to cervical cancer.
宫颈癌的一个主要危险因素是持续性高危型人乳头瘤病毒（HPV）感染，这种病毒可导致宫颈上皮内瘤变。超过 90%的宫颈癌发生在转化区（TZ），这是宫颈内口和外口之间柱状上皮和鳞状上皮交界处的一个小区域。然而，为什么这个区域容易发生恶性进展尚不清楚。我们假设 TZ 区域的细胞更容易发生发育异常分化，这是宫颈癌的前兆。我们使用三维器官型培养来比较源自宫颈外口、TZ 和宫颈内口的 HPV16 永生化上皮细胞系的分化。结果表明，TZ 或宫颈内口的永生化细胞形成的上皮比源自宫颈外口的永生化细胞更具发育异常特征。TZ 和宫颈内口的永生化细胞中，表达增殖标志物 Ki-67 和磷酸化 Akt 的细胞比例更高。TZ 和宫颈内口的永生化细胞能侵袭胶原筏，并表达更高水平的基质金属蛋白酶-1（MMP-1）。抑制 MMP-1 或 Akt 活性可阻断侵袭。综上，我们得出结论，源自 TZ 或宫颈内口的 HPV16 永生化细胞更容易发生发育异常分化，这可能增加了它们发生宫颈癌的易感性。
