The exon 12‐containing LHX6 isoforms promote cervical cancer cell proliferation by regulating the MAPK signaling pathway

LIM homeobox 6 (LHX6) has been reported to be downregulated and inhibits cell proliferation in various cancers. Alternative splicing of LHX6 leads to six annotated isoforms, which can be found in the NCBI database. However, the expression patterns and potential roles of these isoforms remain poorly characterized in cervical cancer. Here, we demonstrated that the LHX6 isoforms containing exon 12 (LHX6(EX(+12)) group) and isoforms lacking exon 12 (LHX6(EX(–12)) group) were differentially expressed in cervical tissue by qRT‐PCR. The mRNA expression level of LHX6(EX(+12)) group was higher than that of LHX6(EX(−12)) group in cervical cancer tissue. Knockdown of LHX6(EX(+12)) group and all LHX6 isoforms (LHX6(All) group) inhibited cell growth, increased cell apoptosis, and induced cell cycle arrest from G0/G1 phase to S phase in vitro. Consistently, overexpression of the LHX6(EX(+12)) group promoted cervical cancer cell proliferation in vitro. In contrast, no significant differences in cell proliferation were found between LHX6(EX(−12)) isoform knockdown group and its control. RNA‐sequencing suggested that the LHX6(EX(+12)) isoform group might exert its cancer‐promoting effects in cervical cancer via regulating MAPK signaling pathway. Downregulation of the LHX6(EX(+12)) group significantly suppressed the phosphorylation of MRK, ERK, JNK, and P38 at the protein level. We also identified some unique biological processes and signaling pathways in which each isoform group might be involved. In summary, our results indicated that LHX6(EX(+12)) isoform group was the dominant oncogenic type of LHX6 in cervical cancer, which may be a new biomarker and a potential precise therapeutic target for cervical cancer in the future.