Ariyoshi Misa, Yuge Ryo, Kitadai Yuki, Shimizu Daisuke, Miyamoto Ryo, Yamashita Ken, Hiyama Yuichi, Takigawa Hidehiko, Urabe Yuji, Oka Shiro
Department of Gastroenterology, Hiroshima University Hospital, Hiroshima 734-0037, Japan.
Cancers (Basel). 2024 Sep 12;16(18):3136. doi: 10.3390/cancers16183136.
Inhibition of WEE1, a key regulator of the G2/M checkpoint of the cell cycle, induces apoptosis by initiating mitosis without repairing DNA damage. However, the effects of WEE1 inhibitors on the tumor immune microenvironment in colorectal cancer (CRC) remain unclear. Here, we investigated the association between WEE1 expression and CRC clinicopathological features using surgically resected CRC specimens and assessed the antitumor effects of a WEE1 inhibitor using CRC cell lines and orthotopic transplantation mouse models. WEE1 expression was not correlated with the clinicopathological features of CRC. The WEE1 inhibitor suppressed cell proliferation in a concentration-dependent manner in all CRC cell lines. It also increased the percentage of cells in the G2/M phase and apoptotic cells, especially in cell lines with mutations, but did not alter these cell percentages in most wild-type cell lines. In the orthotopic mouse model of CRC, tumor volume was significantly reduced in the WEE1 inhibitor-treated group compared to that in the control group. RNA sequencing and immunohistochemistry analyses of mouse tumors revealed that treatment with the WEE1 inhibitor activated tumor immunity and suppressed stromal reactions. These results demonstrate the potential antitumor effects of WEE1 inhibitors in CRC, particularly in patients with mutations.
WEE1是细胞周期G2/M检查点的关键调节因子，抑制WEE1会通过在不修复DNA损伤的情况下启动有丝分裂来诱导细胞凋亡。然而，WEE1抑制剂对结直肠癌（CRC）肿瘤免疫微环境的影响仍不清楚。在此，我们使用手术切除的CRC标本研究了WEE1表达与CRC临床病理特征之间的关联，并使用CRC细胞系和原位移植小鼠模型评估了WEE1抑制剂的抗肿瘤作用。WEE1表达与CRC的临床病理特征无关。WEE1抑制剂在所有CRC细胞系中均以浓度依赖的方式抑制细胞增殖。它还增加了G2/M期细胞和凋亡细胞的百分比，特别是在有 突变的细胞系中，但在大多数野生型细胞系中并未改变这些细胞百分比。在CRC原位小鼠模型中，与对照组相比，WEE1抑制剂治疗组的肿瘤体积显著减小。对小鼠肿瘤的RNA测序和免疫组化分析表明，WEE1抑制剂治疗激活了肿瘤免疫并抑制了基质反应。这些结果证明了WEE1抑制剂在CRC中，特别是在有 突变的患者中的潜在抗肿瘤作用。
