Up-regulation of FAT4 enhances the chemosensitivity of colorectal cancer cells treated by 5-FU

Abstract

Background Colorectal cancer (CRC) has high mortality, and 5-fluorouracil (5-FU) is a common clinical chemotherapeutic drug. The current study aimed to investigate the role of FAT4 in chemosensitivity of CRC cells treated by 5-FU. Methods The immunohistochemistry and qRT-PCR was conducted to measure the FAT4 expression in CRC and adjacent tissues. The FAT4 expression was determined by qRT-PCR and Western blot, comparison of FAT expression between normal and several CRC cell lines was then made, so as to identify cell lines with the highest (LS174T) and the lowest (SW-620) expressions of FAT4 . The effects of 5-FU stimulation at various doses on cell viability were determined by CCK-8, and the level of FAT4 was also measured. After FAT4 knockdown in LS174T or FAT4 overexpression in SW-620 with or without pretreatment of 5-FU (30 µg/mL), cell growth, colony formation, cell migration and invasion, angiogenesis were determined by flow cytometry, wound-healing, transwell assay and tube formation assay, respectively. The expression levels of epithelial-mesenchymal transition (EMT) markers were detected by qRT-PCR and Western blot. Results FAT4 was down-regulated in CRC tissues and cells, cell viability of CRC cells was decreased. The level of FAT4 was increased with the increase of 5-FU concentrations. Moreover, 5-FU stimulation increased FAT4 expression, and reduced cell proliferation, migration, invasion, angiogenesis and cell EMT process, furthermore, such effects of 5-FU stimulation could be enhanced by FAT4 overexpression but reversed by FAT4 knockdown. Conclusions Upregulation of FAT4 could increase the sensitivity of CRC cells to 5-FU.

Prognostic Impact of FSTL3, ADAM12, and FAT4 in Patients of Colon Cancer: Clinicopathologic Study

“…Lack of FAT4 expression was linked with a poor prognosis, deeper invasion, bigger tumor size, and the prevalence of lymphovascular invasion, lymph node, and distant metastases in research by Jiang et al 25 High FAT4 expression was linked with the lack of tumor reappearance and excellent survival rates, according to the findings of the present investigation. These findings are consistent with previous research 13,14,16,24 that showed the antitumor function of FAT4 in a variety of cancers. FAT4 expression’s downregulation was substantially linked to lymph node invasion and poor prognosis in gastric 14 and endometrial cancer 26 .…”

“…FAT4 is believed to prevent EMT in GC and CC cells by E-cadherin expression's up-regulation and VEGF, N-Cadherin, and Vimentin expression's downregulation. 14,24 Lack of FAT4 expression was linked with a poor prognosis, deeper invasion, bigger tumor size, and the prevalence of lymphovascular invasion, lymph node, and distant metastases in research by Jiang et al 25 High FAT4 expression was linked with the lack of tumor reappearance and excellent survival rates, according to the findings of the present investigation. These findings are consistent with previous research 13,14,16,24 that showed the antitumor function of FAT4 in a variety of cancers.…”

“…Disturbances in the Hippo cascade are associated with cancer growth and advancement 23 . In the present investigation, FAT4 expression was much lower in CC tissues than in neighboring tissues, indicating its tumor-suppressive role in numerous cancers 13,14,24 …”

“…23 In the present investigation, FAT4 expression was much lower in CC tissues than in neighboring tissues, indicating its tumor-suppressive role in numerous cancers. 13,14,24 Jiang et al 25 reported that the levels of FAT4 mRNA in cancer tissues were less than in surrounding non-neoplastic stomach tissue. GC cells proliferated, invaded, and migrated more when FAT4 was silenced, providing further evidence of FAT4's tumor suppressor function.…”

“…FAT4 acts as a tumor suppressor and can augment the action of 5-FU in inhibiting the proliferation, invasion, migration, and tube formation of cancerous cervical cervix (CC) cells. 24 It was discovered 27 that elevated nuclear YAP accumulation is correlated with treatment resistance in cancer. It has been established that the reduction of FAT4 results in increased nuclear translocation of YAP, which promotes the migration, proliferation, and advancement of the cell cycle in GC cells.…”